|
1
|
Gonzalez-Prada I, Barcelos Ribeiro A, Dion M, Magariños B, Lapoujade C, Rousseau A, Concheiro A, Garcion E, Alvarez-Lorenzo C. Disulfiram-loaded electrospun fibers with antimicrobial and antitumoral properties for glioblastoma treatment. J Control Release 2025; 381:113615. [PMID: 40086760 DOI: 10.1016/j.jconrel.2025.113615] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 02/02/2025] [Accepted: 03/07/2025] [Indexed: 03/16/2025]
Abstract
Glioblastoma (GB) is a malignant brain tumor with low survival rates and a high recurrence ratio due to limited therapeutic arsenal. The repurposed drug disulfiram (DSF), approved for alcoholism treatment, shows promising anticancer and antimicrobial activity, but its poor biopharmaceutical profile hinders its clinical use. This work aimed to develop DSF-loaded silk fibroin (SF) electrospun fibers for controlled release in the postsurgical resection cavity. Incorporating hydroxypropyl-β-cyclodextrin (HPβCD), which formed inclusion complexes with DSF, enhanced drug release rate and antimicrobial activity (>3 logCFUs reduction) against Staphylococcus aureus and Pseudomonas aeruginosa. Addition of CuCl2 enabled in situ formation of Cu(DDC)2 complexes, further boosting antimicrobial and in vitro antitumoral effects of the nanofibers (≤ 500 nm) while maintaining adequate mechanical properties. Selective toxicity of DSF and DSF-loaded fibers against glioblastoma cells, while sparing against astrocytes, highlights the potential of the nanofibers for targeted brain cancer therapy. Increased potency of DSF at low concentrations when combined with SF fibers, HPβCD and copper was remarkable. Thus, DSF delivery and bioavailability can be significantly optimized through electrospun nanofibers, which may also allow for more precise dosing. Combination with radiotherapy was also explored to assess the translational potential of DSF as part of a combination therapy regimen for glioblastoma. In vivo studies in a rat model simulating GB surgery confirmed the safety of selected formulations in healthy brain tissue. However, findings suggest that DSF-loaded fibers alone may be insufficient for complete tumor eradication, indicating the need for combination with existing therapies to target residual tumor cells effectively.
Collapse
Affiliation(s)
- Iago Gonzalez-Prada
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma (GI-1645), Facultad de Farmacia, Instituto de Materiales (iMATUS) and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, Spain
| | - Arthur Barcelos Ribeiro
- Inserm UMR 1307, CNRS UMR 6075, Université de Nantes, CRCI2NA, Université d'Angers, 49000 Angers, France
| | - Marine Dion
- Inserm UMR 1307, CNRS UMR 6075, Université de Nantes, CRCI2NA, Université d'Angers, 49000 Angers, France
| | - Beatriz Magariños
- Departamento de Microbiología y Parasitología, Facultad de Biología-CIBUS and Aquatic One Health Research Center (iARCUS), Universidade de Santiago de Compostela, Spain
| | - Clémentine Lapoujade
- Inserm UMR 1307, CNRS UMR 6075, Université de Nantes, CRCI2NA, Université d'Angers, 49000 Angers, France
| | - Audrey Rousseau
- Inserm UMR 1307, CNRS UMR 6075, Université de Nantes, CRCI2NA, Université d'Angers, 49000 Angers, France; Department of Pathology, University Hospital of Angers, F-49000 Angers, France
| | - Angel Concheiro
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma (GI-1645), Facultad de Farmacia, Instituto de Materiales (iMATUS) and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, Spain
| | - Emmanuel Garcion
- Inserm UMR 1307, CNRS UMR 6075, Université de Nantes, CRCI2NA, Université d'Angers, 49000 Angers, France; PACEM (Plateforme d'Analyse Cellulaire et Moléculaire), Université d'Angers, SFR 4208, F-49000 Angers, France; PRIMEX (Plateforme de Radiobiologie et d'Imageries Expérimentales), Université d'Angers, SFR 4208, F-49000 Angers, France.
| | - Carmen Alvarez-Lorenzo
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma (GI-1645), Facultad de Farmacia, Instituto de Materiales (iMATUS) and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, Spain.
| |
Collapse
|
|
2
|
Lohse I, Dutcher G, Al-Ali H, Alperstein W, Coulter DW, Trucco M, Trent JC, Wahlestedt C. Drug Sensitivity Testing in Osteosarcoma: A Case Report. Curr Oncol 2025; 32:271. [PMID: 40422530 PMCID: PMC12110314 DOI: 10.3390/curroncol32050271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 04/14/2025] [Accepted: 04/29/2025] [Indexed: 05/28/2025] Open
Abstract
Precision medicine approaches using ex-vivo drug sensitivity testing (DST) have received attention in the cancer research community as a means to improve treatment stratification in populations where multiple treatment attempts are not feasible, or no standard-of-care treatment exists, such as ultra-rare cancers with a significant clinical need for effective treatment options, like osteosarcoma. DST has the potential to supplement existing patient stratification approaches by providing tumor-specific response data to aid in treatment selection at the time of treatment decision. We present the case of a pediatric osteosarcoma patient who was evaluated using DST at the time of standard-of-care treatment to evaluate treatment sensitivity. The DST screen indicated significant treatment sensitivity to anthracyclines and methotrexate, consistent with the first-line standard-of-care therapy (MAP). Clinical follow-up showed treatment sensitivity to standard-of-care MAP treatment and pathology results of 90% necrosis. The present case shows that DST screening is feasible from a technical standpoint, can be performed in a clinically relevant time frame that does not delay treatment start, and provides personalized drug sensitivity information on clinically available agents, and the DST results align with the clinical treatment response.
Collapse
Affiliation(s)
- Ines Lohse
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Molecular Therapeutics Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
- Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Giselle Dutcher
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA; (G.D.); (H.A.-A.); (W.A.); (M.T.); (J.C.T.)
| | - Hassan Al-Ali
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA; (G.D.); (H.A.-A.); (W.A.); (M.T.); (J.C.T.)
- Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Peggy and Harold Katz Family Drug Discovery Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Warren Alperstein
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA; (G.D.); (H.A.-A.); (W.A.); (M.T.); (J.C.T.)
| | - Donald W. Coulter
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Matteo Trucco
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA; (G.D.); (H.A.-A.); (W.A.); (M.T.); (J.C.T.)
| | - Jonathan C. Trent
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA; (G.D.); (H.A.-A.); (W.A.); (M.T.); (J.C.T.)
| | - Claes Wahlestedt
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| |
Collapse
|
|
3
|
Anwer MS, Abdel-Rasol MA, El-Sayed WM. Emerging therapeutic strategies in glioblastsoma: drug repurposing, mechanisms of resistance, precision medicine, and technological innovations. Clin Exp Med 2025; 25:117. [PMID: 40223032 PMCID: PMC11994545 DOI: 10.1007/s10238-025-01631-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Accepted: 03/11/2025] [Indexed: 04/15/2025]
Abstract
Glioblastoma (GBM) is an aggressive Grade IV brain tumor with a poor prognosis. It results from genetic mutations, epigenetic changes, and factors within the tumor microenvironment (TME). Traditional treatments like surgery, radiotherapy, and chemotherapy provide limited survival benefits due to the tumor's heterogeneity and resistance mechanisms. This review examines novel approaches for treating GBM, focusing on repurposing existing medications such as antipsychotics, antidepressants, and statins for their potential anti-GBM effects. Advances in molecular profiling, including next-generation sequencing, artificial intelligence (AI), and nanotechnology-based drug delivery, are transforming GBM diagnosis and treatment. The TME, particularly GBM stem cells and immune evasion, plays a key role in therapeutic resistance. Integrating multi-omics data and applying precision medicine show promise, especially in combination therapies and immunotherapies, to enhance clinical outcomes. Addressing challenges such as drug resistance, targeting GBM stem cells, and crossing the blood-brain barrier is essential for improving treatment efficacy. While current treatments offer limited benefits, emerging strategies such as immunotherapies, precision medicine, and drug repurposing show significant potential. Technologies like liquid biopsies, AI-powered diagnostics, and nanotechnology could help overcome obstacles like the blood-brain barrier and GBM stem cells. Ongoing research into combination therapies, targeted drug delivery, and personalized treatments is crucial. Collaborative efforts and robust clinical trials are necessary to translate these innovations into effective therapies, offering hope for improved survival and quality of life for GBM patients.
Collapse
Affiliation(s)
- Mohamed S Anwer
- Department of Zoology, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt
| | - Mohammed A Abdel-Rasol
- Department of Zoology, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
| | - Wael M El-Sayed
- Department of Zoology, Faculty of Science, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
| |
Collapse
|
|
4
|
Bayoumi M, Youshia J, Arafa MG, Nasr M, Sammour OA. Nanocarriers for the treatment of glioblastoma multiforme: A succinct review of conventional and repositioned drugs in the last decade. Arch Pharm (Weinheim) 2024; 357:e2400343. [PMID: 39074966 DOI: 10.1002/ardp.202400343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/31/2024]
Abstract
Glioblastoma multiforme is a very combative and threatening type of cancer. The standard course of treatment involves excising the tumor surgically, then administering chemotherapy and radiation therapy. Because of the presence of the blood-brain barrier and the unique characteristics of the tumor microenvironment, chemotherapy is extremely difficult and has a high incidence of relapse. With their capacity to precisely target and transport therapeutic medications to the tumor while overcoming the challenges provided by invasive and infiltrative gliomas, nanocarriers offer a potentially beneficial treatment option for gliomas. Drug repositioning or, in other words, finding novel therapeutic uses for medications that have received approval for previous uses has also recently emerged to provide alternative treatments for many diseases, with glioblastoma being among them. In this article, our goal is to shed light on the pathogenesis of glioma and summarize the proposed treatment approaches in the last decade, highlighting how combining repositioned drugs and nanocarriers technology can reduce drug resistance and improve therapeutic efficacy in primary glioma.
Collapse
Affiliation(s)
- Mahitab Bayoumi
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
| | - John Youshia
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Mona G Arafa
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
- Chemotherapeutic Unit, Mansoura University Hospitals, Mansoura, Egypt
- Nanotechnology Research Center, The British University in Egypt, Cairo, Egypt
| | - Maha Nasr
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Omaima A Sammour
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
5
|
Huang J, Campian JL, DeWees TA, Skrott Z, Mistrik M, Johanns TM, Ansstas G, Butt O, Leuthardt E, Dunn GP, Zipfel GJ, Osbun JW, Abraham C, Badiyan S, Schwetye K, Cairncross JG, Rubin JB, Kim AH, Chheda MG. A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma. Int J Radiat Oncol Biol Phys 2024; 120:738-749. [PMID: 38768767 DOI: 10.1016/j.ijrobp.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 04/25/2024] [Accepted: 05/10/2024] [Indexed: 05/22/2024]
Abstract
PURPOSE This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.
Collapse
Affiliation(s)
- Jiayi Huang
- Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri; Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri.
| | - Jian L Campian
- Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri; Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota
| | - Todd A DeWees
- Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri; Department of Computational and Quantitative Medicine, Radiation Oncology, Surgery, Division of Biostatistics, City of Hope, Duarte, California
| | - Zdenek Skrott
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Martin Mistrik
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Tanner M Johanns
- Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri; Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| | - George Ansstas
- Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri; Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| | - Omar Butt
- Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri; Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| | - Eric Leuthardt
- Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri; Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri
| | - Gavin P Dunn
- Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri; Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri
| | - Gregory J Zipfel
- Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri; Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri
| | - Joshua W Osbun
- Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri
| | - Christopher Abraham
- Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri; Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri
| | - Shahed Badiyan
- Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri
| | - Katherine Schwetye
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri
| | - J Gregory Cairncross
- Clark H. Smith Brain Tumour Centre, Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
| | - Joshua B Rubin
- Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri; Department of Neuroscience, Washington University School of Medicine, St Louis, Missouri
| | - Albert H Kim
- Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri; Department of Neurological Surgery, Washington University School of Medicine, St Louis, Missouri
| | - Milan G Chheda
- Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri; Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| |
Collapse
|
|
6
|
Lv H, Yang H, Duan Y, Yan C, Li G, Zhao G, Sun F, Feng Y, Li Y, Fu Y, Li Y, Zhao Z, Jia X. S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine for the treatment of non-small cell lung cancer through regulating NF-κB signalling pathway without neurotoxicity. J Drug Target 2024; 32:1111-1124. [PMID: 38962807 DOI: 10.1080/1061186x.2024.2374037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 06/03/2024] [Accepted: 06/24/2024] [Indexed: 07/05/2024]
Abstract
The discovery of novel targeted agents for non-small cell lung cancer (NSCLC) remains an important research landscape due to the limited efficacy, side effects and drug resistance of current treatment options. Among many repurposed drugs, disulphiram (DSF) has shown the potential to target tumours. However, its unpleasant neurotoxicity greatly limits its use. A DSF derivative, S-(N,N-diethyldithiocarbamoyl)-N-acetyl-l-cysteine (DS-NAC), was synthesised against NSCLC. The therapeutic effects, mechanism and toxicities of DS-NAC were evaluated in A549 and H460 cells and the mouse model of in situ lung cancer. The in vitro results exhibited that DS-NAC had potent anti-proliferation, apoptotic, anti-metastasis and epithelial-mesenchymal transition (EMT) inhibition effects. In the orthotopic lung cancer mouse model, therapeutic effects of DS-NAC were better than those of DSF and were similar to docetaxel (DTX). Also, results from western blot and immunohistochemistry showed that DS-NAC in combination with copper exerted therapeutic effects via regulating NF-κB signalling pathway and ROS-related proteins such as HIF-1α, Nrf2 and PKC-δ rather than regulating ROS level directly. Moreover, the safety evaluation study showed that DS-NAC had low haematologic and hepatic toxicities in comparison with DTX as well as low neurological toxicity compared with DSF. DS-NAC could be a promising anti-lung cancer agent with a favourable safety profile.
Collapse
Affiliation(s)
- Huaiyou Lv
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Pharmacy, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, China
| | - Huatian Yang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yifei Duan
- Department of Statistics, University of Virginia, Charlottesville, VA, USA
| | - Chongzheng Yan
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Genju Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Guozhi Zhao
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fengqin Sun
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yafei Feng
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yuhan Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yaqing Fu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yizhe Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zhongxi Zhao
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, China
- School of Pharmaceutical Sciences, Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiumei Jia
- Department of Pharmacy, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, China
| |
Collapse
|
|
7
|
Lv H, Yang H, Duan Y, Sha H, Zhao Z. A disulfiram derivative against lung cancer via the Notch signaling pathway without neurotoxicity and hepatotoxicity. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4747-4760. [PMID: 38147104 DOI: 10.1007/s00210-023-02906-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/11/2023] [Indexed: 12/27/2023]
Abstract
The exploration of novel anti-lung cancer small-molecule drugs is important for drug resistance and adverse effects of chemotherapeutic drugs in current clinics. Disulfiram (DSF), as an antidote, has been proven to have excellent antitumor effects in combination with copper (Cu). However, the risk for potential neurotoxicity and hepatotoxicity in clinical use, as well as its poor water solubility, limits its use. In this study, we identified a DSF derivative, S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine, which could greatly increase the water solubility by converting it to a calcium salt (DS-NAC). The anti-lung cancer pharmacodynamic studies in vitro of DS-NAC were evaluated and a mouse model of lung cancer in situ was established to explore the therapeutic effects of DS-NAC compared with DSF and oxaliplatin (OXA). The results demonstrated that DS-NAC combined with Cu had superior cytotoxicity to DSF and OXA in the CCK8 assay against lung cancer cells, and exhibited potent anti-metastatic, epithelial-mesenchymal transition inhibition. In addition, DS-NAC showed better antitumor effects than DSF and comparable effects to OXA in lung cancer in situ model. In terms of the antitumor mechanism, we discovered that DS-NAC in combination with Cu exerted a greater inhibitory effect on the Notch pathway than DSF, which may account for its excellent antitumor effects. Finally, we verified the safety of DS-NAC in vivo, showing lower hepatotoxicity and neurotoxicity compared with DSF and OXA. DS-NAC is a promising anti-lung cancer drug with a favorable safety profile.
Collapse
Affiliation(s)
- Huaiyou Lv
- Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Key University Laboratory of Pharmaceutics &, Drug Delivery Systems of Shandong Province, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Department of Pharmacy, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264001, Shandong, China
| | - Huatian Yang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Key University Laboratory of Pharmaceutics &, Drug Delivery Systems of Shandong Province, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Yifei Duan
- Department of Statistics, University of Virginia, Charlottesville, VA, USA
| | - Hongyu Sha
- Department of Pharmacy, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264001, Shandong, China.
| | - Zhongxi Zhao
- Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Key University Laboratory of Pharmaceutics &, Drug Delivery Systems of Shandong Province, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
| |
Collapse
|
|
8
|
Zeng M, Wu B, Wei W, Jiang Z, Li P, Quan Y, Hu X. Disulfiram: A novel repurposed drug for cancer therapy. Chin Med J (Engl) 2024; 137:1389-1398. [PMID: 38275022 PMCID: PMC11188872 DOI: 10.1097/cm9.0000000000002909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Indexed: 01/27/2024] Open
Abstract
ABSTRACT Cancer is a major global health issue. Effective therapeutic strategies can prolong patients' survival and reduce the costs of treatment. Drug repurposing, which identifies new therapeutic uses for approved drugs, is a promising approach with the advantages of reducing research costs, shortening development time, and increasing efficiency and safety. Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug used to treat chronic alcoholism, has a great potential as an anticancer drug by targeting diverse human malignancies. Several studies show the antitumor effects of DSF, particularly the combination of DSF and copper (DSF/Cu), on a wide range of cancers such as glioblastoma (GBM), breast cancer, liver cancer, pancreatic cancer, and melanoma. In this review, we summarize the antitumor mechanisms of DSF/Cu, including induction of intracellular reactive oxygen species (ROS) and various cell death signaling pathways, and inhibition of proteasome activity, as well as inhibition of nuclear factor-kappa B (NF-κB) signaling. Furthermore, we highlight the ability of DSF/Cu to target cancer stem cells (CSCs), which provides a new approach to prevent tumor recurrence and metastasis. Strikingly, DSF/Cu inhibits several molecular targets associated with drug resistance, and therefore it is becoming a novel option to increase the sensitivity of chemo-resistant and radio-resistant patients. Studies of DSF/Cu may shed light on its improved application to clinical tumor treatment.
Collapse
Affiliation(s)
- Min Zeng
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Baibei Wu
- The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Wenjie Wei
- Institute of Biochemistry of Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Zihan Jiang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Peiqiang Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Yuanting Quan
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xiaobo Hu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
- The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| |
Collapse
|
|
9
|
Weth FR, Hoggarth GB, Weth AF, Paterson E, White MPJ, Tan ST, Peng L, Gray C. Unlocking hidden potential: advancements, approaches, and obstacles in repurposing drugs for cancer therapy. Br J Cancer 2024; 130:703-715. [PMID: 38012383 PMCID: PMC10912636 DOI: 10.1038/s41416-023-02502-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 60.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 10/30/2023] [Accepted: 11/13/2023] [Indexed: 11/29/2023] Open
Abstract
High rates of failure, exorbitant costs, and the sluggish pace of new drug discovery and development have led to a growing interest in repurposing "old" drugs to treat both common and rare diseases, particularly cancer. Cancer, a complex and heterogeneous disease, often necessitates a combination of different treatment modalities to achieve optimal outcomes. The intrinsic polygenicity of cancer, intricate biological signalling networks, and feedback loops make the inhibition of a single target frequently insufficient for achieving the desired therapeutic impact. As a result, addressing these complex or "smart" malignancies demands equally sophisticated treatment strategies. Combinatory treatments that target the multifaceted oncogenic signalling network hold immense promise. Repurposed drugs offer a potential solution to this challenge, harnessing known compounds for new indications. By avoiding the prohibitive costs and long development timelines associated with novel cancer drugs, this approach holds the potential to usher in more effective, efficient, and cost-effective cancer treatments. The pursuit of combinatory therapies through drug repurposing may hold the key to achieving superior outcomes for cancer patients. However, drug repurposing faces significant commercial, technological and regulatory challenges that need to be addressed. This review explores the diverse approaches employed in drug repurposing, delves into the challenges faced by the drug repurposing community, and presents innovative solutions to overcome these obstacles. By emphasising the significance of combinatory treatments within the context of drug repurposing, we aim to unlock the full potential of this approach for enhancing cancer therapy. The positive aspects of drug repurposing in oncology are underscored here; encompassing personalized treatment, accelerated development, market opportunities for shelved drugs, cancer prevention, expanded patient reach, improved patient access, multi-partner collaborations, increased likelihood of approval, reduced costs, and enhanced combination therapy.
Collapse
Affiliation(s)
- Freya R Weth
- Gillies McIndoe Research Institute, Newtown, Wellington, 6021, New Zealand
- Centre for Biodiscovery and School of Biological Sciences, Victoria University of Wellington, Kelburn, Wellington, 6021, New Zealand
| | - Georgia B Hoggarth
- Gillies McIndoe Research Institute, Newtown, Wellington, 6021, New Zealand
| | - Anya F Weth
- Gillies McIndoe Research Institute, Newtown, Wellington, 6021, New Zealand
| | - Erin Paterson
- Gillies McIndoe Research Institute, Newtown, Wellington, 6021, New Zealand
| | | | - Swee T Tan
- Gillies McIndoe Research Institute, Newtown, Wellington, 6021, New Zealand
- Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Lower Hutt, 5040, New Zealand
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Lifeng Peng
- Centre for Biodiscovery and School of Biological Sciences, Victoria University of Wellington, Kelburn, Wellington, 6021, New Zealand
| | - Clint Gray
- Gillies McIndoe Research Institute, Newtown, Wellington, 6021, New Zealand.
- Centre for Biodiscovery and School of Biological Sciences, Victoria University of Wellington, Kelburn, Wellington, 6021, New Zealand.
| |
Collapse
|
|
10
|
Mohi-Ud-Din R, Chawla A, Sharma P, Mir PA, Potoo FH, Reiner Ž, Reiner I, Ateşşahin DA, Sharifi-Rad J, Mir RH, Calina D. Repurposing approved non-oncology drugs for cancer therapy: a comprehensive review of mechanisms, efficacy, and clinical prospects. Eur J Med Res 2023; 28:345. [PMID: 37710280 PMCID: PMC10500791 DOI: 10.1186/s40001-023-01275-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 08/08/2023] [Indexed: 09/16/2023] Open
Abstract
Cancer poses a significant global health challenge, with predictions of increasing prevalence in the coming years due to limited prevention, late diagnosis, and inadequate success with current therapies. In addition, the high cost of new anti-cancer drugs creates barriers in meeting the medical needs of cancer patients, especially in developing countries. The lengthy and costly process of developing novel drugs further hinders drug discovery and clinical implementation. Therefore, there has been a growing interest in repurposing approved drugs for other diseases to address the urgent need for effective cancer treatments. The aim of this comprehensive review is to provide an overview of the potential of approved non-oncology drugs as therapeutic options for cancer treatment. These drugs come from various chemotherapeutic classes, including antimalarials, antibiotics, antivirals, anti-inflammatory drugs, and antifungals, and have demonstrated significant antiproliferative, pro-apoptotic, immunomodulatory, and antimetastatic properties. A systematic review of the literature was conducted to identify relevant studies on the repurposing of approved non-oncology drugs for cancer therapy. Various electronic databases, such as PubMed, Scopus, and Google Scholar, were searched using appropriate keywords. Studies focusing on the therapeutic potential, mechanisms of action, efficacy, and clinical prospects of repurposed drugs in cancer treatment were included in the analysis. The review highlights the promising outcomes of repurposing approved non-oncology drugs for cancer therapy. Drugs belonging to different therapeutic classes have demonstrated notable antitumor effects, including inhibiting cell proliferation, promoting apoptosis, modulating the immune response, and suppressing metastasis. These findings suggest the potential of these repurposed drugs as effective therapeutic approaches in cancer treatment. Repurposing approved non-oncology drugs provides a promising strategy for addressing the urgent need for effective and accessible cancer treatments. The diverse classes of repurposed drugs, with their demonstrated antiproliferative, pro-apoptotic, immunomodulatory, and antimetastatic properties, offer new avenues for cancer therapy. Further research and clinical trials are warranted to explore the full potential of these repurposed drugs and optimize their use in treating various cancer types. Repurposing approved drugs can significantly expedite the process of identifying effective treatments and improve patient outcomes in a cost-effective manner.
Collapse
Affiliation(s)
- Roohi Mohi-Ud-Din
- Department of General Medicine, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, 190001, India
| | - Apporva Chawla
- Khalsa College of Pharmacy, G.T. Road, Amritsar, Punjab, 143001, India
| | - Pooja Sharma
- Khalsa College of Pharmacy, G.T. Road, Amritsar, Punjab, 143001, India
| | - Prince Ahad Mir
- Khalsa College of Pharmacy, G.T. Road, Amritsar, Punjab, 143001, India
| | - Faheem Hyder Potoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, 1982, 31441, Dammam, Saudi Arabia
| | - Željko Reiner
- Department of Internal Medicine, School of Medicine, University Hospital Center Zagreb, Zagreb, Croatia
| | - Ivan Reiner
- Department of Nursing Sciences, Catholic University of Croatia, Ilica 242, 10000, Zagreb, Croatia
| | - Dilek Arslan Ateşşahin
- Baskil Vocational School, Department of Plant and Animal Production, Fırat University, 23100, Elazıg, Turkey
| | | | - Reyaz Hassan Mir
- Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, Kashmir, 190006, India.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
| |
Collapse
|
|
11
|
Chang MR, Rusanov DA, Arakelyan J, Alshehri M, Asaturova AV, Kireeva GS, Babak MV, Ang WH. Targeting emerging cancer hallmarks by transition metal complexes: Cancer stem cells and tumor microbiome. Part I. Coord Chem Rev 2023. [DOI: 10.1016/j.ccr.2022.214923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
|
|
12
|
Zhong S, Shengyu Liu, Xin Shi, Zhang X, Li K, Liu G, Li L, Tao S, Zheng B, Sheng W, Ye Z, Xing Q, Zhai Q, Ren L, Wu Y, Bao Y. Disulfiram in glioma: Literature review of drug repurposing. Front Pharmacol 2022; 13:933655. [PMID: 36091753 PMCID: PMC9448899 DOI: 10.3389/fphar.2022.933655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Gliomas are the most common malignant brain tumors. High-grade gliomas, represented by glioblastoma multiforme (GBM), have a poor prognosis and are prone to recurrence. The standard treatment strategy is tumor removal combined with radiotherapy and chemotherapy, such as temozolomide (TMZ). However, even after conventional treatment, they still have a high recurrence rate, resulting in an increasing demand for effective anti-glioma drugs. Drug repurposing is a method of reusing drugs that have already been widely approved for new indication. It has the advantages of reduced research cost, safety, and increased efficiency. Disulfiram (DSF), originally approved for alcohol dependence, has been repurposed for adjuvant chemotherapy in glioma. This article reviews the drug repurposing method and the progress of research on disulfiram reuse for glioma treatment.
Collapse
|
|
13
|
Jin P, Jiang J, Zhou L, Huang Z, Nice EC, Huang C, Fu L. Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management. J Hematol Oncol 2022; 15:97. [PMID: 35851420 PMCID: PMC9290242 DOI: 10.1186/s13045-022-01313-4] [Citation(s) in RCA: 111] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 06/29/2022] [Indexed: 02/08/2023] Open
Abstract
Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.
Collapse
Affiliation(s)
- Ping Jin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Jingwen Jiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China.
| | - Li Fu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Health Science Center, Shenzhen, 518060, Guangdong, People's Republic of China.
| |
Collapse
|
|
14
|
Solovieva M, Shatalin Y, Odinokova I, Krestinina O, Baburina Y, Mishukov A, Lomovskaya Y, Pavlik L, Mikheeva I, Holmuhamedov E, Akatov V. Disulfiram oxy-derivatives induce entosis or paraptosis-like death in breast cancer MCF-7 cells depending on the duration of treatment. Biochim Biophys Acta Gen Subj 2022; 1866:130184. [PMID: 35660414 DOI: 10.1016/j.bbagen.2022.130184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/26/2022] [Accepted: 05/28/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Dithiocarbamates and derivatives (including disulfiram, DSF) are currently investigated as antineoplastic agents. We have revealed earlier the ability of hydroxocobalamin (vitamin В12b) combined with diethyldithiocarbamate (DDC) to catalyze the formation of highly cytotoxic oxidized derivatives of DSF (DSFoxy, sulfones and sulfoxides). METHODS Electron and fluorescent confocal microscopy, molecular biology and conventional biochemical techniques were used to study the morphological and functional responses of MCF-7 human breast cancer cells to treatment with DDC and B12b alone or in combination. RESULTS DDC induces unfolded protein response in MCF-7 cells. The combined use of DDC and B12b causes MCF-7 cell death. Electron microscopy revealed the separation of ER and nuclear membranes, leading to the formation of both cytoplasmic and perinuclear vacuoles, with many fibers inside. The process of vacuolization coincided with the appearance of ER stress markers, a marked damage to mitochondria, a significant inhibition of 20S proteasome, and actin depolimerization at later stages. Specific inhibitors of apoptosis, necroptosis, autophagy, and ferroptosis did not prevent cell death. A short- time (6-h) exposure to DSFoxy caused a significant increase in the number of entotic cells. CONCLUSIONS These observations indicate that MCF-7 cells treated with a mixture of DDC and B12b die by the mechanism of paraptosis. A short- time exposure to DSFoxy caused, along with paraptosis, a significant activation of the entosis and its final stage, lysosomal cell death. GENERAL SIGNIFICANCE The results obtained open up opportunities for the development of new approaches to induce non-apoptotic death of cancer cells by dithiocarbamates.
Collapse
Affiliation(s)
- Marina Solovieva
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Yuri Shatalin
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia.
| | - Irina Odinokova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Olga Krestinina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Yulia Baburina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Artem Mishukov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia; Laboratory of Biorheology and Biomechanics, Center for Theoretical Problems of Physicochemical Pharmacology RAS, Moscow 109029, Russian Federation
| | - Yana Lomovskaya
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Liubov Pavlik
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Irina Mikheeva
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Ekhson Holmuhamedov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia; Department of Pharmacology, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Vladimir Akatov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| |
Collapse
|
|
15
|
Kannappan V, Liu Y, Wang Z, Azar K, Kurusamy S, Kilari RS, Armesilla AL, Morris MR, Najlah M, Liu P, Bian XW, Wang W. PLGA-nano-encapsulated Disulfiram inhibits hypoxia-induced NFκB, cancer stem cells and targets glioblastoma in vitro and in vivo. Mol Cancer Ther 2022; 21:1273-1284. [PMID: 35579893 DOI: 10.1158/1535-7163.mct-22-0066] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/02/2022] [Accepted: 05/10/2022] [Indexed: 11/16/2022]
Abstract
Glioblastoma stem cell (GSC) is the major cause of glioblastoma multiforme (GBM) chemotherapy failure. Hypoxia is one of the determinants of GSC. NFκB plays a pivotal link between hypoxia and cancer stem cells (CSCs). Disulfiram (DS), an antialcoholism drug, has very strong NFκB-inhibiting and anti-CSC activity. In this study, the in vitro anti-GSC activity of DS and in vivo anti-GBM efficacy of poly lactic-co-glycolic acid nanoparticle-encapsulated DS (DS-PLGA) were examined. We attempt to elucidate the molecular network between hypoxia and GSCs, and also examined the anti-GSC activity of DS in vitro and in vivo. The influence of GSCs and hypoxia on GBM chemoresistance and invasiveness was studied in hypoxic and spheroid cultures. The molecular regulatory roles of NFκB, HIF1α and HIF2α were investigated using stably transfected U373MG cell lines. The hypoxia in neurospheres determines the cancer stem cell characters of the sphere-cultured GBM cell lines (U87MG, U251MG, U373MG). NFκB is located at a higher hierarchical position than HIF1α/HIF2α in hypoxic regulatory network and plays a key role in hypoxia-induced GSC characters. DS inhibits NFκB activity and targets hypoxia-induced GSCs. It showed selective toxicity to GBM cells, eradicates GSC and blocks migration and invasion at very low concentrations. DS-PLGA efficaciously inhibits orthotopic and subcutaneous U87MG xenograft in mouse models with no toxicity to vital organs.
Collapse
Affiliation(s)
| | - Ying Liu
- Queen Mary University of London, London, United Kingdom
| | | | - Karim Azar
- University of Wolverhampton, Wolverhampton, United Kingdom
| | | | | | | | - Mark R Morris
- University of Wolverhampton, Wolverhampoton, United Kingdom
| | | | - Peng Liu
- Queen Mary University of London, LONDON, United Kingdom
| | - Xiu-Wu Bian
- Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Weiguang Wang
- University of Wolverhampton, Wolverhampton, United Kingdom
| |
Collapse
|
|
16
|
Sun F, Wang H, Nie J, Hong B. Repurposing disulfiram as a chemo-therapeutic sensitizer: molecular targets and mechanisms. Anticancer Agents Med Chem 2022; 22:2920-2926. [PMID: 35430981 DOI: 10.2174/1871520621666220415102553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/20/2021] [Accepted: 02/03/2022] [Indexed: 11/22/2022]
Abstract
Currently, chemo-therapy is still the main strategy for cancer treatment. However, chemo-therapy resistance remains its main challenge. Disulfiram [DSF] is a drug approved by FDA for the treatment of alcohol addiction, but it is later discovered that it has the anticancer activity. Importantly, there have been many literatures reporting that DSF can be used as a chemo-therapeutic sensitizer to enhance the anticancer activity of chemo-drugs in a variety of cancers. Furthermore, the combinations of DSF and chemo-drugs have been tested in clinic trials. In the review, we summarized the possible molecular targets and mechanisms of DSF to reverse chemo-resistance. We also further discussed the opportunities and challenges of DSF as a chemo-therapeutic sensitizer. In conclusion, DSF could be a potential repurposed drug to sensitize cancer cells to chemo-therapy in clinic.
Collapse
Affiliation(s)
- Feilong Sun
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.,University of Science and Technology of China, Hefei, Anhui, China
| | - Hongzhi Wang
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.,Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, China
| | - Jinfu Nie
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.,Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, China
| | - Bo Hong
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.,Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, China
| |
Collapse
|
|
17
|
Wang W, Han S, Gao W, Feng Y, Li K, Wu D. Long Noncoding RNA KCNQ1OT1 Confers Gliomas Resistance to Temozolomide and Enhances Cell Growth by Retrieving PIM1 From miR-761. Cell Mol Neurobiol 2022; 42:695-708. [PMID: 32897512 PMCID: PMC11441228 DOI: 10.1007/s10571-020-00958-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/30/2020] [Indexed: 12/17/2022]
Abstract
Many studies have found that the dysregulation of long noncoding RNA (lncRNA) contributed to cancer initiation, progression, and recurrence via multiple signaling pathways. However, the underlying mechanisms of lncRNA in temozolomide (TMZ)-resistant gliomas were not well understood, hindering the improvement of TMZ-based therapies. The present study demonstrated that the lncRNA KCNQ1OT1 increased in TMZ-resistant glioma cells compared to the TMZ-sensitive cells. The introduction of KCNQ1OT1 promoted cell viability, clonogenicity, and rhodamine 123 efflux while hampering TMZ-induced apoptosis. Moreover, KCNQ1OT1 directly sponged miR-761, which decreased in TMZ-resistant sublines. The overexpression of miR-761 attenuated cell viability and clonogenicity, while triggering apoptosis and rhodamine 123 accumulation post-TMZ exposure, leading to a response to TMZ. The interaction between miR-761 and 3'-untranslated region of PIM1 attenuated PIM1-mediated signaling cascades. Furthermore, the knockdown of KCNQ1OT1 augmented the TMZ-induced tumor regression in TMZ-resistant U251 mouse models. Briefly, the present study evaluated that KCNQ1OT1 conferred TMZ resistance by releasing PIM1 expression from miR-761, resulting in the upregulation of PIM-mediated MDR1, c-Myc, and Survivin. The present findings demonstrated that the interplay of KCNQ1OT1: miR-761: PIM1 regulated chemoresistance in gliomas and provided a promising therapeutic target for TMZ-resistant glioma patients.
Collapse
Affiliation(s)
- Wei Wang
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People's Republic of China
| | - Shuai Han
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People's Republic of China
| | - Wei Gao
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People's Republic of China
| | - Yuan Feng
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People's Republic of China
| | - Kunhang Li
- Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People's Republic of China
| | - Di Wu
- Department of Tumor Biotherapy and Cancer Research, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, People's Republic of China.
| |
Collapse
|
|
18
|
Drug Repurposing for Glioblastoma and Current Advances in Drug Delivery-A Comprehensive Review of the Literature. Biomolecules 2021; 11:biom11121870. [PMID: 34944514 PMCID: PMC8699739 DOI: 10.3390/biom11121870] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/19/2021] [Accepted: 12/03/2021] [Indexed: 12/22/2022] Open
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel anti-neoplastic drugs from bench to bedside can incur significant time and cost implications. Drug repurposing may help overcome that obstacle. A wide range of drugs that are already approved for clinical use for the treatment of other diseases have been found to target GBM-associated signaling pathways and are being repurposed for the treatment of GBM. While many of these drugs are undergoing pre-clinical testing, others are in the clinical trial phase. Since GBM stem cells (GSCs) have been found to be a main source of tumor recurrence after surgery, recent studies have also investigated whether repurposed drugs that target these pathways can be used to counteract tumor recurrence. While several repurposed drugs have shown significant efficacy against GBM cell lines, the blood–brain barrier (BBB) can limit the ability of many of these drugs to reach intratumoral therapeutic concentrations. Localized intracranial delivery may help to achieve therapeutic drug concentration at the site of tumor resection while simultaneously minimizing toxicity and side effects. These strategies can be considered while repurposing drugs for GBM.
Collapse
|
|
19
|
Liu T, Xie XL, Zhou X, Chen SX, Wang YJ, Shi LP, Chen SJ, Wang YJ, Wang SL, Zhang JN, Dou SY, Jiang XY, Cui RL, Jiang HQ. Y-box binding protein 1 augments sorafenib resistance via the PI3K/Akt signaling pathway in hepatocellular carcinoma. World J Gastroenterol 2021; 27:4667-4686. [PMID: 34366628 PMCID: PMC8326262 DOI: 10.3748/wjg.v27.i28.4667] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/04/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown.
AIM To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC.
METHODS The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq).
RESULTS YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance.
CONCLUSION Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.
Collapse
Affiliation(s)
- Ting Liu
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Xiao-Li Xie
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Xue Zhou
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Sheng-Xiong Chen
- Department of Hepatobiliary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Yi-Jun Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Lin-Ping Shi
- Department of Gastroenterology, Hebei General Hospital, Shijiazhuang 050000, Hebei Province, China
| | - Shu-Jia Chen
- Department of Gastroenterology, Shijiazhuang People’s Hospital, Shijiazhuang 050000, Hebei Province, China
| | - Yong-Juan Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Shu-Ling Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Jiu-Na Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Shi-Ying Dou
- Department of Infectious Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Xiao-Yu Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Ruo-Lin Cui
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Hui-Qing Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| |
Collapse
|
|
20
|
Yamashita D, Bernstock JD, Elsayed G, Sadahiro H, Mohyeldin A, Chagoya G, Ilyas A, Mooney J, Estevez-Ordonez D, Yamaguchi S, Flanary VL, Hackney JR, Bhat KP, Kornblum HI, Zamboni N, Kim SH, Chiocca EA, Nakano I. Targeting glioma-initiating cells via the tyrosine metabolic pathway. J Neurosurg 2021; 134:721-732. [PMID: 32059178 PMCID: PMC8447888 DOI: 10.3171/2019.11.jns192028] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 11/19/2019] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Despite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism. METHODS Comprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 glioma-initiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry. RESULTS Metabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core. CONCLUSIONS Selective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies.
Collapse
Affiliation(s)
- Daisuke Yamashita
- Department of Neurosurgery, University of Alabama at Birmingham, Alabama
| | - Joshua D. Bernstock
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Galal Elsayed
- Department of Neurosurgery, University of Alabama at Birmingham, Alabama
| | - Hirokazu Sadahiro
- Department of Neurosurgery, University of Alabama at Birmingham, Alabama
- Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan
| | - Ahmed Mohyeldin
- Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio
| | - Gustavo Chagoya
- Department of Neurosurgery, University of Alabama at Birmingham, Alabama
| | - Adeel Ilyas
- Department of Neurosurgery, University of Alabama at Birmingham, Alabama
| | - James Mooney
- Department of Neurosurgery, University of Alabama at Birmingham, Alabama
| | | | - Shinobu Yamaguchi
- Department of Neurosurgery, University of Alabama at Birmingham, Alabama
| | | | - James R. Hackney
- Departments of Pathology, University of Alabama at Birmingham, Alabama
| | - Krishna P. Bhat
- Department of Translational Molecular Pathology and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Harley I. Kornblum
- Departments of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior
- Broad Stem Cell Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Nicola Zamboni
- Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
| | - Sung-Hak Kim
- Department of Neurosurgery, University of Alabama at Birmingham, Alabama
- Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju
- Gwangju Center, Korea Basic Science Institute, Gwangju, Republic of Korea
| | - E. Antonio Chiocca
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Ichiro Nakano
- Department of Neurosurgery, University of Alabama at Birmingham, Alabama
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Alabama
| |
Collapse
|
|
21
|
Lu C, Li X, Ren Y, Zhang X. Disulfiram: a novel repurposed drug for cancer therapy. Cancer Chemother Pharmacol 2021; 87:159-172. [PMID: 33426580 DOI: 10.1007/s00280-020-04216-8] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023]
Abstract
Cancer is a major health issue worldwide and the global burden of cancer is expected to reduce the costs of treatment as well as prolong the survival time. One of the promising approaches is drug repurposing, because it reduces costs and shortens the production cycle of research and development. Disulfiram (DSF), which was originally approved as an anti-alcoholism drug, has been proven safe and shows the potential to target tumours. Its anti-tumour effect has been reported in many preclinical studies and recently on seven types of cancer in humans: non-small cell lung cancer (NSCLC), liver cancer, breast cancer, prostate cancer, pancreatic cancer, glioblastoma (GBM) and melanoma and has a successful breakthrough in the treatment of NSCLC and GBM. The mechanisms, particularly the intracellular signalling pathways, still remain to be completely elucidated. As shown in our previous study, DSF inhibits NF-kB signalling, proteasome activity, and aldehyde dehydrogenase (ALDH) activity. It induces endoplasmic reticulum (ER) stress and autophagy and has been used as an adjuvant therapy with irradiation or chemotherapy drugs. On the other hand, DSF not only kills the normal cancer cells but also has the ability to target cancer stem cells, which provides a new approach to prevent tumour recurrence and metastasis. Furthermore, other researchers have reported the ability of DSF to bind to nuclear protein localization protein 4 (NPL4), induce its immobilization and dysfunction, ultimately leading to cell death. Here, we provide an overview of DSF repurposing as a treatment in preclinical studies and clinical trials, and review studies describing the mechanisms underlying its anti-neoplastic effects.
Collapse
Affiliation(s)
- Chen Lu
- Key Laboratory of Antibody Technology, National Health Commission, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu, China
| | - Xinyan Li
- Key Laboratory of Antibody Technology, National Health Commission, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu, China
| | - Yongya Ren
- Key Laboratory of Antibody Technology, National Health Commission, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu, China
| | - Xiao Zhang
- Key Laboratory of Antibody Technology, National Health Commission, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu, China.
| |
Collapse
|
|
22
|
Tang C, Liu D, Fan Y, Yu J, Li C, Su J, Wang C. Visualization and bibliometric analysis of cAMP signaling system research trends and hotspots in cancer. J Cancer 2021; 12:358-370. [PMID: 33391432 PMCID: PMC7738981 DOI: 10.7150/jca.47158] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 10/02/2020] [Indexed: 12/13/2022] Open
Abstract
Cyclic adenosine monophosphate (cAMP) is an essential second messenger that widely distributed among prokaryotic and eukaryotic organisms. cAMP can regulate various biological processes, including cell proliferation, differentiation, apoptosis and immune functions. Any dysregulation or alteration of cAMP signaling may cause cell metabolic disorder, immune dysfunction and lead to disease or cancer. This study aimed to conduct a scientometric analysis of cAMP signaling system in cancer field, and explored the research trend, hotspots and frontiers from the past decade. Relevant literatures published from 2009 to 2019 were collected in the Web of Science Core Collection database. EndNote X9 was used to remove duplicate articles, and irrelevant articles were manually filtered. Bibliometric analyses were completed by CiteSpace V. A total of 4306 articles were included in this study. The number of related literatures published each year is gradually increasing. Most of them belong to “Biochemistry & Molecular Biology”, “Oncology”, “Cell Biology”, “Pharmacology & Pharmacy” and “Endocrinology & Metabolism” areas. In the past decade, USA, China, and Japan contributed the most to the research of cAMP signaling system in cancer. The frontiers and hotspots of cAMP signaling pathway system related to cancer fields mainly focused on cancer cell apoptosis, metastasis, and multiple tumors occurrence in patients with Carney complex. Intervention of the cAMP metabolic pathway may be a potential and promising therapeutic strategy for controlling clinical cancer and tumor diseases.
Collapse
Affiliation(s)
- Caoli Tang
- Department of Preventive Medicine, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, China
| | - Duanya Liu
- Department of Preventive Medicine, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, China
| | - Yongsheng Fan
- Department of Preventive Medicine, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, China
| | - Jun Yu
- Department of Preventive Medicine, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, China
| | - Cong Li
- Department of Preventive Medicine, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, China
| | - Jianmei Su
- Department of Preventive Medicine, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, China.,Key Laboratory of Regional Development and Environmental Response, Faculty of Resources and Environmental Science, Hubei University, Friendship Avenue 368, Wuhan 430062, Hubei, China
| | - Chunhong Wang
- Department of Preventive Medicine, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, China
| |
Collapse
|
|
23
|
Zhao Y, Lin Z, Lin Z, Zhou C, Liu G, Lin J, Zhang D, Lin D. Overexpression of Mucin 1 Suppresses the Therapeutical Efficacy of Disulfiram against Canine Mammary Tumor. Animals (Basel) 2020; 11:ani11010037. [PMID: 33375426 PMCID: PMC7823863 DOI: 10.3390/ani11010037] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/14/2020] [Accepted: 12/23/2020] [Indexed: 01/03/2023] Open
Abstract
Simple Summary Canine mammary tumor is one of the most prevalent canine tumor types in China. Clinical studies showed that the high expression of mucin 1 (MUC1) protein is significantly associated with the malignancy and poor prognosis of canine mammary tumor. Therefore, it is worthwhile to investigate the expression of mucin 1 in developing treatments against canine mammary tumors. In the present study, it is demonstrated that disulfiram, an approved medication in treating human alcoholism, also has inhibitory effects on the growth of canine mammary tumor cells both in vitro and in vivo. With the overexpression of MUC1, the inhibitory effects of disulfiram decrease accordingly. Moreover, disulfiram is shown to inhibit phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (Akt) signaling transduction, which is attenuated by MUC1 overexpression. Overall, these results indicate that the expression level of MUC1 is detrimental to determining the anti-tumor activity of disulfiram. Further consideration should be given when treating the canine mammary tumor with disulfiram or other PI3K/Akt inhibitors. Abstract Mucin 1 (MUC1), a transmembrane protein, is closely associated with the malignancy and metastasis of canine mammary tumors; however, the role of overexpressed MUC1 in the development of cancer cells and response to drug treatment remains unclear. To address this question, we developed a new canine mammary tumor cell line, CIPp-MUC1, with an elevated expression level of MUC1. In vitro studies showed that CIPp-MUC1 cells are superior in proliferation and migration than wild-type control, which was associated with the upregulation of PI3K, p-Akt, mTOR, Bcl-2. In addition, overexpression of MUC1 in CIPp-MUC1 cells inhibited the suppressing activity of disulfiram on the growth and metastasis of tumor cells, as well as inhibiting the pro-apoptotic effect of disulfiram. In vivo studies, on the other side, showed more rapid tumor growth and stronger resistance to disulfiram treatment in CIPp-MUC1 xenograft mice than in wild-type control. In conclusion, our study demonstrated the importance of MUC1 in affecting the therapeutical efficiency of disulfiram against canine mammary tumors, indicating that the expression level of MUC1 should be considered for clinical use of disulfiram or other drugs targeting PI3K/Akt pathway.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Di Zhang
- Correspondence: (D.Z.); (D.L.); Tel.: +86-1369-326-2510 (D.Z.); +86-1380-105-8458 (D.L.)
| | - Degui Lin
- Correspondence: (D.Z.); (D.L.); Tel.: +86-1369-326-2510 (D.Z.); +86-1380-105-8458 (D.L.)
| |
Collapse
|
|
24
|
Wang R, Shen J, Yan H, Gao X, Dong T, Wang P, Zhou J. The Evolving Role of Disulfiram in Radiobiology and the Treatment of Breast Cancer. Onco Targets Ther 2020; 13:10441-10446. [PMID: 33116623 PMCID: PMC7569069 DOI: 10.2147/ott.s271532] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 08/29/2020] [Indexed: 12/15/2022] Open
Abstract
Disulfiram (DSF), also known as “Antabuse”, has been widely used in clinical practice to treat alcoholism. In the past decades, both in vivo and in vitro experiments showed that DSF has strong anti-cancer activity, there were some clinical studies indicated the administration of this drug was associated with favorable survival in breast cancer. It is also evident that DSF has a radioprotective effect on normal cells and could be utilized during the course of radiation therapy. Moreover, increasing evidences demonstrated the role of DSF in enhancing the radiosensitivity of tumor cells in number of alternative mechanisms. Recent studies have also elaborated the anticancer mechanism of DSF in tumor cells. This review summarizes the anticancer activity of DSF both in preclinical studies and clinical trials, focuses on the advances of this drug in radiobiology and the treatment of breast cancer, and reveals the promising of repurposing DSF as a novel radiosensitizer and radioprotector in further clinical trials.
Collapse
Affiliation(s)
- Rui Wang
- Department of Surgery, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Jun Shen
- Department of Surgery, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Huanhuan Yan
- Department of Surgery, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Xitao Gao
- Department of Surgery, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Tianfu Dong
- Department of Surgery, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Peishun Wang
- Department of Surgery, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Jun Zhou
- Department of Surgery, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| |
Collapse
|
|
25
|
Qu Y, Sun X, Ma L, Li C, Xu Z, Ma W, Zhou Y, Zhao Z, Ma D. Therapeutic effect of disulfiram inclusion complex embedded in hydroxypropyl-β-cyclodextrin on intracranial glioma-bearing male rats via intranasal route. Eur J Pharm Sci 2020; 156:105590. [PMID: 33065226 DOI: 10.1016/j.ejps.2020.105590] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 11/16/2022]
Abstract
The unique environment of brain poses a huge challenge for drug development aimed at combatting glioblastoma (GBM) due to poor organ targeting. Intranasal administration is often considered as an attractive route directly into brain by not only circumventing the blood brain barrier and but also avoiding the hepatic first-pass effect. Disulfiram (DSF) is an old alcohol-aversion drug that has anti-tumor activities against diverse cancer types such as GBM in preclinical studies, especially when it is combined with cupper ion (Cu). In this study, DSF was embedded in hydroxypropyl-β-cyclodextrin (HP-β-CD) to prepare a DSF inclusion complex with the enhanced solubility, anti-GBM activity and high safety in vitro. The highest fluorescence signal of Cy5.5/HP-β-CD in the male rat brains showed the strong brain-targeting of nose-to-brain drug delivery. Therapeutic effects of DSF/HP-β-CD combined with Cu (DSF/HP-β-CD/Cu) on intracranial glioma-bearing male rats via different drug delivery routes were then investigated. DSF/HP-β-CD/Cu administrated by the intranasal route effectively inhibited tumor growth and migration, promoted apoptosis, and achieved 36.8% and 18.2% prolonged median survival time comparing to those of model rats by oral and intravenous administrations, respectively. Moreover, no obvious histopathological damage to normal tissues was observed by H&E staining. Overall, DSF/HP-β-CD/Cu could be a promising intranasal formulation for the effective GBM treatment.
Collapse
Affiliation(s)
- Ying Qu
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China; Shandong Key University Laboratory of Pharmaceutics & Drug Delivery Systems, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China
| | - Xiao Sun
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China; Shandong Key University Laboratory of Pharmaceutics & Drug Delivery Systems, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China
| | - Long Ma
- The Testing Center of Shandong Bureau of China Metallurgical Geology Bureau, 14 Shanshidong Road, Jinan, Shandong, 250100, China
| | - Chunyan Li
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China; Shandong Key University Laboratory of Pharmaceutics & Drug Delivery Systems, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China
| | - Zixuan Xu
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China; Shandong Key University Laboratory of Pharmaceutics & Drug Delivery Systems, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China
| | - Wenqing Ma
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China; Shandong Key University Laboratory of Pharmaceutics & Drug Delivery Systems, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China
| | - Yingying Zhou
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China; Shandong Key University Laboratory of Pharmaceutics & Drug Delivery Systems, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China
| | - Zhongxi Zhao
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China; Shandong Key University Laboratory of Pharmaceutics & Drug Delivery Systems, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China.
| | - Dedong Ma
- Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, China
| |
Collapse
|
|
26
|
La Manna F, De Menna M, Patel N, Karkampouna S, De Filippo MR, Klima I, Kloen P, Beimers L, Thalmann GN, Pelger RCM, Jacinto E, Kruithof-de Julio M. Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity. Front Oncol 2020; 10:1012. [PMID: 32656088 PMCID: PMC7324765 DOI: 10.3389/fonc.2020.01012] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 05/21/2020] [Indexed: 12/11/2022] Open
Abstract
Bone metastasis is the leading cause of prostate cancer (PCa) mortality, frequently marking the progression to castration-resistant PCa. Dysregulation of the androgen receptor pathway is a common feature of castration-resistant PCa, frequently appearing in association with mTOR pathway deregulations. Advanced PCa is also characterized by increased tumor heterogeneity and cancer stem cell (CSC) frequency. CSC-targeted therapy is currently being explored in advanced PCa, with the aim of reducing cancer clonal divergence and preventing disease progression. In this study, we compared the molecular pathways enriched in a set of bone metastasis from breast and prostate cancer from snap-frozen tissue. To further model PCa drug resistance mechanisms, we used two patient-derived xenografts (PDX) models of bone-metastatic PCa, BM18, and LAPC9. We developed in vitro organoids assay and ex vivo tumor slice drug assays to investigate the effects of mTOR- and CSC-targeting compounds. We found that both PDXs could be effectively targeted by treatment with the bivalent mTORC1/2 inhibitor Rapalink-1. Exposure of LAPC9 to Rapalink-1 but not to the CSC-targeting drug disulfiram blocked mTORC1/2 signaling, diminished expression of metabolic enzymes involved in glutamine and lipid metabolism and reduced the fraction of CD44+ and ALDEFluorhigh cells, in vitro. Mice treated with Rapalink-1 showed a significantly delayed tumor growth compared to control and cells recovered from the tumors of treated animals showed a marked decrease of CD44 expression. Taken together these results highlight the increased dependence of advanced PCa on the mTOR pathway, supporting the development of a targeted approach for advanced, bone metastatic PCa.
Collapse
Affiliation(s)
- Federico La Manna
- Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
- Department of Urology, Leiden University Medical Center, Leiden, Netherlands
| | - Marta De Menna
- Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
| | - Nikhil Patel
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
| | - Sofia Karkampouna
- Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
| | - Maria Rosaria De Filippo
- Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
- Institute of Pathology and Medical Genetics, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Irena Klima
- Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
| | - Peter Kloen
- Department of Orthopedic Trauma Surgery, Academic Medical Center, Amsterdam, Netherlands
| | - Lijkele Beimers
- Department of Orthopedic Surgery, MC Slotervaart, Amsterdam, Netherlands
| | - George N. Thalmann
- Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Rob C. M. Pelger
- Department of Urology, Leiden University Medical Center, Leiden, Netherlands
| | - Estela Jacinto
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
| | - Marianna Kruithof-de Julio
- Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
- Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland
| |
Collapse
|
|
27
|
Yang Q, Yao Y, Li K, Jiao L, Zhu J, Ni C, Li M, Dou QP, Yang H. An Updated Review of Disulfiram: Molecular Targets and Strategies for Cancer Treatment. Curr Pharm Des 2020; 25:3248-3256. [PMID: 31419930 DOI: 10.2174/1381612825666190816233755] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 08/06/2019] [Indexed: 12/31/2022]
Abstract
Repurposing already approved drugs as new anticancer agents is a promising strategy considering the advantages such as low costs, low risks and less time-consumption. Disulfiram (DSF), as the first drug for antialcoholism, was approved by the U.S. Food and Drug Administration (FDA) over 60 years ago. Increasing evidence indicates that DSF has great potential for the treatment of various human cancers. Several mechanisms and targets of DSF related to cancer therapy have been proposed, including the inhibition of ubiquitin-proteasome system (UPS), cancer cell stemness and cancer metastasis, and alteration of the intracellular reactive oxygen species (ROS). This article provides a brief review about the history of the use of DSF in humans and its molecular mechanisms and targets of anticancer therapy, describes DSF delivery strategies for cancer treatment, summarizes completed and ongoing cancer clinical trials involving DSF, and offers strategies to better use DSF in cancer therapies.
Collapse
Affiliation(s)
- Qingzhu Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yao Yao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Kai Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Lin Jiao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Jiazhen Zhu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Cheng Ni
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Mengmeng Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Q Ping Dou
- Departments of Oncology, Pharmacology and Pathology, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, United States
| | - Huanjie Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| |
Collapse
|
|
28
|
Ren L, Feng W, Shao J, Ma J, Xu M, Zhu BZ, Zheng N, Liu S. Diethyldithiocarbamate-copper nanocomplex reinforces disulfiram chemotherapeutic efficacy through light-triggered nuclear targeting. Am J Cancer Res 2020; 10:6384-6398. [PMID: 32483459 PMCID: PMC7255023 DOI: 10.7150/thno.45558] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 04/22/2020] [Indexed: 12/24/2022] Open
Abstract
To circumvent the huge cost, long R&D time and the difficulty to identify the targets of new drugs, repurposing the ones that have been clinically approved has been considered as a viable strategy to treat different diseases. In the current study, we outlined the rationale for repurposing disulfiram (DSF, an old alcohol-aversion drug) to treat primary breast cancer and its metastases. Methods: To overcome a few shortcomings of the individual administration of DSF, such as the dependence on copper ions (Cu2+) and limited capability in selective targeting, we here artificially synthesized the active form of DSF, diethyldithiocarbamate (DTC)-Cu complex (CuET) for cancer therapeutics. To achieve a greater efficacy in vivo, smart nanomedicines were devised through a one-step self-assembly of three functional components including a chemically stable and biocompatible phase-change material (PCM), the robust anticancer drug (CuET) and a near-infrared (NIR) dye (DIR), namely CuET/DIR NPs. A number of in vitro assays were performed including the photothermal efficacy, light-triggered drug release behavior, nuclear localization, DNA damage and induction of apoptosis of CuET/DIR NPs and molecular mechanisms underlying CuET-induced repression on cancer metastatic behaviors. Meanwhile, the mice bearing 4T1-LG12-drived orthotopic tumors were employed to evaluate in vivo biodistribution and anti-tumor effect of CuET/DIR NPs. The intravenous injection model was employed to reflect the changes of the intrinsic metastatic propensity of 4T1-LG12 cells responding to CuET/DIR NPs. Results: The rationally designed nanomedicines have self-traceability for bioimaging, long blood circulation time for enhanced drug accumulation in the tumor site and photo-responsive release of the anticancer drugs. Moreover, our data unearthed that CuET/DIR nanomedicines behave like “Trojan horse” to transport CuET into the cytoplasm, realizing substantial intracellular accumulation. Upon NIR laser irradiation, massive CuET would be triggered to release from the nanomedicines and reach a high local concentration towards the nucleus, where the pro-apoptotic effects were conducted. Importantly, our CuET/DIR nanomedicines revealed a pronounced capability to leash breast cancer metastases through inhibition on EMT. Additionally, these nanomedicines showed great biocompatibility in animals. Conclusion: These combined data unearthed a remarkably enhanced tumor-killing efficacy of our CuET nanomedicines through nuclear targeting. This work may open a new research area of repurposing DSF as innovative therapeutic agents to treat breast cancer and its metastases.
Collapse
|
|
29
|
Armando RG, Gómez DLM, Gomez DE. New drugs are not enough‑drug repositioning in oncology: An update. Int J Oncol 2020; 56:651-684. [PMID: 32124955 PMCID: PMC7010222 DOI: 10.3892/ijo.2020.4966] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 12/16/2019] [Indexed: 11/24/2022] Open
Abstract
Drug repositioning refers to the concept of discovering novel clinical benefits of drugs that are already known for use treating other diseases. The advantages of this are that several important drug characteristics are already established (including efficacy, pharmacokinetics, pharmacodynamics and toxicity), making the process of research for a putative drug quicker and less costly. Drug repositioning in oncology has received extensive focus. The present review summarizes the most prominent examples of drug repositioning for the treatment of cancer, taking into consideration their primary use, proposed anticancer mechanisms and current development status.
Collapse
Affiliation(s)
- Romina Gabriela Armando
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Bernal B1876, Argentina
| | - Diego Luis Mengual Gómez
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Bernal B1876, Argentina
| | - Daniel Eduardo Gomez
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Bernal B1876, Argentina
| |
Collapse
|
|
30
|
Ekinci E, Rohondia S, Khan R, Dou QP. Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents. Recent Pat Anticancer Drug Discov 2020; 14:113-132. [PMID: 31084595 DOI: 10.2174/1574892814666190514104035] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 04/30/2019] [Accepted: 05/10/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity. OBJECTIVE To summarize the anti-cancer effects of Disulfiram through a thorough patent review. METHODS This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy. RESULTS Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug. CONCLUSION For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.
Collapse
Affiliation(s)
- Elmira Ekinci
- Departments of Oncology, Pharmacology & Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, United States
| | - Sagar Rohondia
- Departments of Oncology, Pharmacology & Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, United States
| | - Raheel Khan
- Departments of Oncology, Pharmacology & Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, United States
| | - Qingping P Dou
- Departments of Oncology, Pharmacology & Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, United States
| |
Collapse
|
|
31
|
Sharma HS, Muresanu DF, Castellani RJ, Nozari A, Lafuente JV, Tian ZR, Sahib S, Bryukhovetskiy I, Bryukhovetskiy A, Buzoianu AD, Patnaik R, Wiklund L, Sharma A. Pathophysiology of blood-brain barrier in brain tumor. Novel therapeutic advances using nanomedicine. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 151:1-66. [PMID: 32448602 DOI: 10.1016/bs.irn.2020.03.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
32
|
Vengoji R, Ponnusamy MP, Rachagani S, Mahapatra S, Batra SK, Shonka N, Macha MA. Novel therapies hijack the blood-brain barrier to eradicate glioblastoma cancer stem cells. Carcinogenesis 2019; 40:2-14. [PMID: 30475990 DOI: 10.1093/carcin/bgy171] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 10/12/2018] [Accepted: 11/21/2018] [Indexed: 12/11/2022] Open
Abstract
Glioblastoma (GBM) is amongst the most aggressive brain tumors with a dismal prognosis. Despite significant advances in the current multimodality therapy including surgery, postoperative radiotherapy (RT) and temozolomide (TMZ)-based concomitant and adjuvant chemotherapy (CT), tumor recurrence is nearly universal with poor patient outcomes. These limitations are in part due to poor drug penetration through the blood-brain barrier (BBB) and resistance to CT and RT by a small population of cancer cells recognized as tumor-initiating cells or cancer stem cells (CSCs). Though CT and RT kill the bulk of the tumor cells, they fail to affect CSCs, resulting in their enrichment and their development into more refractory tumors. Therefore, identifying the mechanisms of resistance and developing therapies that specifically target CSCs can improve response, prevent the development of refractory tumors and increase overall survival of GBM patients. Small molecule inhibitors that can breach the BBB and selectively target CSCs are emerging. In this review, we have summarized the recent advancements in understanding the GBM CSC-specific signaling pathways, the CSC-tumor microenvironment niche that contributes to CT and RT resistance and the use of novel combination therapies of small molecule inhibitors that may be used in conjunction with TMZ-based chemoradiation for effective management of GBM.
Collapse
Affiliation(s)
- Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Nicole Shonka
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Muzafar A Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Department of Otolaryngology/Head and Neck Surgery, University of Nebraska Medical Center, Omaha, NE, USA
| |
Collapse
|
|
33
|
Allen SA, Datta S, Sandoval J, Tomilov A, Sears T, Woolard K, Angelastro JM, Cortopassi GA. Cetylpyridinium chloride is a potent AMP-activated kinase (AMPK) inducer and has therapeutic potential in cancer. Mitochondrion 2019; 50:19-24. [PMID: 31654752 DOI: 10.1016/j.mito.2019.09.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 09/21/2019] [Accepted: 09/23/2019] [Indexed: 12/25/2022]
Abstract
AMP-activated protein kinase (AMPK) is a eukaryotic energy sensor and protector from mitochondrial/energetic stress that is also a therapeutic target for cancer and metabolic disease. Metformin is an AMPK inducer that has been used in cancer therapeutic trials. Through screening we isolated cetylpyridinium chloride (CPC), a drug known to dose-dependently inhibit mitochondrial complex 1, as a potent and dose-dependent AMPK stimulator. Mitochondrial biogenesis and bioenergetics changes have also been implicated in glioblastoma, which is the most aggressive form of brain tumors. Cetylpyridinium chloride has been administered in humans as a safe drug-disinfectant for several decades, and we report here that under in vitro conditions, cetylpyridinium chloride kills glioblastoma cells in a dose dependent manner at a higher efficacy compared to current standard of care drug, temozolomide.
Collapse
Affiliation(s)
- Sonia A Allen
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA 95616, USA.
| | - Sandipan Datta
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA 95616, USA.
| | - Jose Sandoval
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA 95616, USA.
| | - Alexey Tomilov
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA 95616, USA.
| | - Thomas Sears
- Department of Pathology, Microbiology, and Immunology, 4206 Veterinary Medicine Dr., VM3A, UC Davis, CA 95616, USA.
| | - Kevin Woolard
- Department of Pathology, Microbiology, and Immunology, 4206 Veterinary Medicine Dr., VM3A, UC Davis, CA 95616, USA.
| | - James M Angelastro
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA 95616, USA.
| | - Gino A Cortopassi
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA 95616, USA.
| |
Collapse
|
|
34
|
Xie X, Urabe G, Marcho L, Stratton M, Guo LW, Kent CK. ALDH1A3 Regulations of Matricellular Proteins Promote Vascular Smooth Muscle Cell Proliferation. iScience 2019; 19:872-882. [PMID: 31513972 PMCID: PMC6739626 DOI: 10.1016/j.isci.2019.08.044] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 06/09/2019] [Accepted: 08/21/2019] [Indexed: 01/24/2023] Open
Abstract
Vascular smooth muscle cell (VSMC) proliferation promotes intimal hyperplasia (IH) in occluding vascular diseases. Here we identified a positive role of ALDH1A3 (an aldehyde dehydrogenase) in this pro-IH process. The expression of ALDH1A3, but not that of 18 other isoforms of the ALDH family, was substantially increased in cytokine-stimulated VSMCs. PDGF(BB) stimulated VSMC total ALDH activity and proliferation, whereas ALDH1A3 silencing abolished this effect. ALDH1A3 silencing also diminished the expression of two matricellular proteins (TNC1 and ESM1), revealing a previously unrecognized ALDH1A3 function. Loss-of-function experiments demonstrated that TNC1 and ESM1 mediated ALDH1A3's pro-proliferative function via activation of AKT/mTOR and/or MEK/ERK pathways. Furthermore, ALDH inhibition with disulfiram blocked VSMC proliferation/migration in vitro and decreased TNC1 and ESM1 and IH in angioplasty-injured rat carotid arteries. Thus, ALDH1A3 promotes VSMC proliferation at least partially through TNC1/ESM1 upregulation; dampening excessive ALDH1A3 activity represents a potential approach to IH mitigation.
The ALDH1A3 isoform promotes vascular smooth muscle cell proliferation ALDH1A3's function is mediated by its upregulation of TNC1 and ESM1 The pan-ALDH inhibitor drug disulfiram mitigates intimal hyperplasia
Collapse
Affiliation(s)
- Xiujie Xie
- Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Go Urabe
- Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Lynn Marcho
- Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Matthew Stratton
- Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Lian-Wang Guo
- Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
| | - Craig K Kent
- Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
| |
Collapse
|
|
35
|
Affiliation(s)
- Shiqun Shao
- Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of EducationCollege of Chemical and Biological Engineering, Zhejiang University Hangzhou 310027 China
| | - Jingxing Si
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang ProvinceClinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College Hangzhou 310014 China
| | - Youqing Shen
- Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of EducationCollege of Chemical and Biological Engineering, Zhejiang University Hangzhou 310027 China
| |
Collapse
|
|
36
|
Huang H, Jiang R, Lian Z, Zhang W, Hu Z, Hu D. miR-222/GAS5 is involved in DNA damage and cytotoxic effects induced by temozolomide in T98G cell line. J Appl Toxicol 2018; 39:726-734. [PMID: 30575081 DOI: 10.1002/jat.3762] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 10/31/2018] [Accepted: 11/12/2018] [Indexed: 12/24/2022]
Abstract
Temozolomide (TMZ), a therapeutic DNA alkylator that can cause lethal DNA damage in cancer cells, is widely used for the standard chemotherapy against glioblastoma. However, long-term treatment with TMZ often causes drug resistance and poor prognosis, the mechanism of which remains largely unclear. This study aimed to investigate the possible role of miR-222/GAS5 axis on DNA damage and cytotoxic effects induced by TMZ in glioblastoma cells (T98G). Data suggest that the DNA comet tail length of T98G is positively correlated with the levels of miR-222 (R2 = 0.9808, P < 0.05), and negatively correlated with the levels of GAS5 (R2 = 0.8903, P < 0.05). The optical density value of T98G is negatively correlated with the levels of miR-222 (R2 = 0.7848, P < 0.05), and positively correlated with the levels of GAS5 (R2 = 0.6886, P < 0.05). Furthermore, comet tail length and optical density value are negatively and positively correlated with the levels of O-6-methylguanine-DNA methyltransferase, respectively (R2 = 0.8462, P < 0.05; R2 = 0.7018, P < 0.05). In conclusion, miR-222/GAS5 is involved in DNA damage and cytotoxic effects induced by TMZ, which means that miR-222/GAS5 may have great potential of being used as a biomarker for screening of chemotherapeutic alkylators.
Collapse
Affiliation(s)
- Haoyu Huang
- Department of Environmental Health, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangdong Province, Guangzhou, 510515, China
| | - Ran Jiang
- Department of Environmental Health, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangdong Province, Guangzhou, 510515, China
| | - Zhenwei Lian
- Department of Environmental Health, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangdong Province, Guangzhou, 510515, China
| | - Wenjuan Zhang
- Department of Toxicology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Zuqing Hu
- School of Medicine, Jiamusi University, Heilongjiang Province, Jiamusi, 154007, China
| | - Dalin Hu
- Department of Environmental Health, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangdong Province, Guangzhou, 510515, China
| |
Collapse
|
|
37
|
Tao Z, Li T, Ma H, Yang Y, Zhang C, Hai L, Liu P, Yuan F, Li J, Yi L, Tong L, Wang Y, Xie Y, Ming H, Yu S, Yang X. Autophagy suppresses self-renewal ability and tumorigenicity of glioma-initiating cells and promotes Notch1 degradation. Cell Death Dis 2018; 9:1063. [PMID: 30337536 PMCID: PMC6194143 DOI: 10.1038/s41419-018-0957-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 06/01/2018] [Accepted: 06/06/2018] [Indexed: 01/05/2023]
Abstract
Autophagy is a vital process that involves degradation of long-lived proteins and dysfunctional organelles and contributes to cellular metabolism. Glioma-initiating cells (GICs) have the ability to self-renew, differentiate into heterogeneous types of tumor cells, and sustain tumorigenicity; thus, GICs lead to tumor recurrence. Accumulating evidence indicates that autophagy can induce stem cell differentiation and increase the lethality of temozolomide against GICs. However, the mechanism underlying the regulation of GIC self-renewal by autophagy remains uncharacterized. In the present study, autophagy induced by AZD8055 and rapamycin treatment suppressed GIC self-renewal in vitro. We found that autophagy inhibited Notch1 pathway activation. Moreover, autophagy activated Notch1 degradation, which is associated with maintenance of the self-renewal ability of GICs. Furthermore, autophagy abolished the tumorigenicity of CD133 + U87-MG neurosphere cells in an intracranial model. These findings suggest that autophagy regulating GICs self-renewal and tumorigenicity is probably bound up with Notch1 degradation. The results of this study could aid in the design of autophagy-based clinical trials for glioma treatments, which may be of great value.
Collapse
Affiliation(s)
- Zhennan Tao
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China.,Key Laboratory of Post-trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, 300052, China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
| | - Tao Li
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China.,Key Laboratory of Post-trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, 300052, China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
| | - Haiwen Ma
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China.,Key Laboratory of Post-trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, 300052, China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
| | - Yihan Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China.,Key Laboratory of Post-trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, 300052, China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
| | - Chen Zhang
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Long Hai
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China.,Key Laboratory of Post-trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, 300052, China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
| | - Peidong Liu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Feng Yuan
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China.,Key Laboratory of Post-trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, 300052, China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
| | - Jiabo Li
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China.,Key Laboratory of Post-trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, 300052, China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
| | - Li Yi
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China.,Key Laboratory of Post-trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, 300052, China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
| | - Luqing Tong
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China.,Key Laboratory of Post-trauma Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, 300052, China.,Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
| | - Yingshuai Wang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Yang Xie
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Haolang Ming
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Shengping Yu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Xuejun Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| |
Collapse
|
|
38
|
Drug Repurposing of Metabolic Agents in Malignant Glioma. Int J Mol Sci 2018; 19:ijms19092768. [PMID: 30223473 PMCID: PMC6164672 DOI: 10.3390/ijms19092768] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 12/21/2022] Open
Abstract
Gliomas are highly invasive brain tumors with short patient survival. One major pathogenic factor is aberrant tumor metabolism, which may be targeted with different specific and unspecific agents. Drug repurposing is of increasing interest in glioma research. Drugs interfering with the patient’s metabolism may also influence glioma metabolism. In this review, we outline definitions and methods for drug repurposing. Furthermore, we give insights into important candidates for a metabolic drug repurposing, namely metformin, statins, non-steroidal anti-inflammatory drugs, disulfiram and lonidamine. Advantages and pitfalls of drug repurposing will finally be discussed.
Collapse
|
|
39
|
Barbieri F, Würth R, Pattarozzi A, Verduci I, Mazzola C, Cattaneo MG, Tonelli M, Solari A, Bajetto A, Daga A, Vicentini LM, Mazzanti M, Florio T. Inhibition of Chloride Intracellular Channel 1 (CLIC1) as Biguanide Class-Effect to Impair Human Glioblastoma Stem Cell Viability. Front Pharmacol 2018; 9:899. [PMID: 30186163 PMCID: PMC6110922 DOI: 10.3389/fphar.2018.00899] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 07/23/2018] [Indexed: 12/20/2022] Open
Abstract
The antidiabetic biguanide metformin exerts antiproliferative effects in different solid tumors. However, during preclinical studies, metformin concentrations required to induce cell growth arrest were invariably within the mM range, thus difficult to translate in a clinical setting. Consequently, the search for more potent metformin derivatives is a current goal for new drug development. Although several cell-specific intracellular mechanisms contribute to the anti-tumor activity of metformin, the inhibition of the chloride intracellular channel 1 activity (CLIC1) at G1/S transition is a key events in metformin antiproliferative effect in glioblastoma stem cells (GSCs). Here we tested several known biguanide-related drugs for the ability to affect glioblastoma (but not normal) stem cell viability, and in particular: phenformin, a withdrawn antidiabetic drug; moroxydine, a former antiviral agent; and proguanil, an antimalarial compound, all of them possessing a linear biguanide structure as metformin; moreover, we evaluated cycloguanil, the active form of proguanil, characterized by a cyclized biguanide moiety. All these drugs caused a significant impairment of GSC proliferation, invasiveness, and self-renewal reaching IC50 values significantly lower than metformin, (range 0.054–0.53 mM vs. 9.4 mM of metformin). All biguanides inhibited CLIC1-mediated ion current, showing the same potency observed in the antiproliferative effects, with the exception of proguanil which was ineffective. These effects were specific for GSCs, since no (or little) cytotoxicity was observed in normal umbilical cord mesenchymal stem cells, whose viability was not affected by metformin and moroxydine, while cycloguanil and phenformin induced toxicity only at much higher concentrations than required to reduce GSC proliferation or invasiveness. Conversely, proguanil was highly cytotoxic also for normal mesenchymal stem cells. In conclusion, the inhibition of CLIC1 activity represents a biguanide class-effect to impair GSC viability, invasiveness, and self-renewal, although dissimilarities among different drugs were observed as far as potency, efficacy and selectivity as CLIC1 inhibitors. Being CLIC1 constitutively active in GSCs, this feature is relevant to grant the molecules with high specificity toward GSCs while sparing normal cells. These results could represent the basis for the development of novel biguanide-structured molecules, characterized by high antitumor efficacy and safe toxicological profile.
Collapse
Affiliation(s)
- Federica Barbieri
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Roberto Würth
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Alessandra Pattarozzi
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Ivan Verduci
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy
| | - Chiara Mazzola
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy
| | - Maria G Cattaneo
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy
| | - Michele Tonelli
- Dipartimento di Farmacia, Università di Genova, Genova, Italy
| | - Agnese Solari
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Adriana Bajetto
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy
| | - Antonio Daga
- IRCCS, Ospedale Policlinico San Martino, Genova, Italy
| | - Lucia M Vicentini
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy
| | - Michele Mazzanti
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy
| | - Tullio Florio
- Sezione di Farmacologia, Dipartimento di Medicina Interna and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova, Genova, Italy.,IRCCS, Ospedale Policlinico San Martino, Genova, Italy
| |
Collapse
|
|
40
|
Kong Y, Ai C, Dong F, Xia X, Zhao X, Yang C, Kang C, Zhou Y, Zhao Q, Sun X, Wu X. Targeting of BMI-1 with PTC-209 inhibits glioblastoma development. Cell Cycle 2018; 17:1199-1211. [PMID: 29886801 PMCID: PMC6110607 DOI: 10.1080/15384101.2018.1469872] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 04/13/2018] [Indexed: 01/16/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor and refractory to existing therapies. The oncogene BMI-1, a member of Polycomb Repressive Complex 1 (PRC1) plays essential roles in various human cancers and becomes an attractive therapeutic target. Here we showed that BMI-1 is highly expressed in GBM and especially enriched in glioblastoma stem cells (GSCs). Then we comprehensively investigated the anti-GBM effects of PTC-209, a novel specific inhibitor of BMI-1. We found that PTC-209 efficiently downregulates BMI-1 expression and the histone H2AK119ub1 levels at microM concentrations. In vitro, PTC-209 effectively inhibits glioblastoma cell proliferation and migration, and GSC self-renewal. Transcriptomic analyses of TCGA datasets of glioblastoma and PTC-209-treated GBM cells demonstrate that PTC-209 reverses the altered transcriptional program associated with BMI-1 overexpression. And Chromatin Immunoprecipitation assay confirms that the derepressed tumor suppressor genes belong to BMI-1 targets and the enrichment levels of H2AK119ub1 at their promoters is decreased upon PTC-209 treatment. Strikingly, the glioblastoma growth is significantly attenuated by PTC-209 in a murine orthotopic xenograft model. Therefore our study provides proof-of-concept for inhibitors targeting BMI-1 in potential applications as an anti-GBM therapy.
Collapse
MESH Headings
- Animals
- Brain Neoplasms/genetics
- Brain Neoplasms/pathology
- Carcinogenesis/drug effects
- Carcinogenesis/pathology
- Cell Cycle Checkpoints/drug effects
- Cell Cycle Checkpoints/genetics
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Movement/genetics
- Cell Proliferation/drug effects
- Cell Proliferation/genetics
- Cell Self Renewal/drug effects
- Disease Progression
- Female
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Glioblastoma/genetics
- Glioblastoma/pathology
- Heterocyclic Compounds, 2-Ring/chemistry
- Heterocyclic Compounds, 2-Ring/pharmacology
- Humans
- Mice, Inbred BALB C
- Mice, Nude
- Molecular Targeted Therapy
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Polycomb Repressive Complex 1/antagonists & inhibitors
- Polycomb Repressive Complex 1/genetics
- Polycomb Repressive Complex 1/metabolism
- Promoter Regions, Genetic/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Thiazoles/chemistry
- Thiazoles/pharmacology
- Transcription, Genetic/drug effects
- Up-Regulation/drug effects
- Up-Regulation/genetics
Collapse
Affiliation(s)
- Yu Kong
- Department of Cell Biology, Tianjin Medical University, Tianjin, China
- Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Chunbo Ai
- Department of Cell Biology, Tianjin Medical University, Tianjin, China
| | - Feng Dong
- Department of Cell Biology, Tianjin Medical University, Tianjin, China
| | - Xianyou Xia
- Department of Cell Biology, Tianjin Medical University, Tianjin, China
| | - Xiujuan Zhao
- Department of Cell Biology, Tianjin Medical University, Tianjin, China
| | - Chao Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Neurological Institute, Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China
| | - Chunsheng Kang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Neurological Institute, Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China
| | - Yan Zhou
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences at Wuhan University, Wuhan, China
| | - Qian Zhao
- Department of Cell Biology, Tianjin Medical University, Tianjin, China
| | - Xiujing Sun
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Xudong Wu
- Department of Cell Biology, Tianjin Medical University, Tianjin, China
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| |
Collapse
|
|
41
|
Bai J, Xiao L, Tao Z, Cao B, Han Y, Fan W, Kong X, Ma X, Gao Y, Bi L, Chen W, Shi B, Liu X. Ectopic expression of E3 ubiquitin-protein ligase 2 in glioma and enhances resistance to apoptosis through activating nuclear factor κ-light-chain-enhancer of B cells. Oncol Lett 2018; 16:4391-4399. [PMID: 30214574 PMCID: PMC6126155 DOI: 10.3892/ol.2018.9153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 03/07/2018] [Indexed: 12/31/2022] Open
Abstract
Nuclear factor κ-light-chain-enhancer of B cells (NF-κB) is one of the most important tumorigenic factors. Although it has been established that NF-κB is overly activated in human glioma cells, the molecular mechanisms that lead to the signal transduction to NF-κB and thereby the induction of resistance to apoptosis remain poorly understood. The present study demonstrated that mRNA and protein levels of E3 ubiquitin-protein ligase 2 (MIB2) were markedly upregulated in glioma cell lines and clinical samples. Immunohistochemical analysis also revealed high levels of MIB2 expression in glioma specimens. Ectopic overexpression of MIB2 was established in glioma cell lines to investigate its fundamental roles in the response of human glioma to apoptotic inducers. The results indicated that ultraviolet irradiation-induced cell apoptosis was inhibited with MIB2 overexpression in glioma cells. Notably, knockdown of MIB2 using RNA interference was able to increase the sensitivity of glioma cells to the pro-apoptotic agents. The present study identified that MIB2 induces NF-κB activation and facilitates the resistance of glioma cell to apoptosis. It was proposed that MIB2 may not only be an important hallmark to glioma disease progression, but that it may also offer novel clinical strategies to overcome resistance to cancer therapies.
Collapse
Affiliation(s)
- Jian Bai
- Institute of Organ Transplantation, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China.,Experimental Animal Centre, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110032, P.R. China
| | - Li Xiao
- Institute of Organ Transplantation, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| | - Zhen Tao
- Department of Neurosurgery, General Hospital of Jinan Military Command, Jinan, Shandong 250031, P.R. China
| | - Bingzhen Cao
- Experimental Animal Centre, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110032, P.R. China
| | - Yong Han
- Institute of Organ Transplantation, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| | - Wenmei Fan
- Institute of Organ Transplantation, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| | - Xiangrui Kong
- Institute of Organ Transplantation, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| | - Xihui Ma
- Institute of Organ Transplantation, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| | - Yu Gao
- Institute of Organ Transplantation, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| | - Lili Bi
- Institute of Organ Transplantation, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| | - Wen Chen
- Institute of Organ Transplantation, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| | - Bingyi Shi
- Institute of Organ Transplantation, The 309th Hospital of Chinese People's Liberation Army, Beijing 100091, P.R. China
| | - Xicheng Liu
- Department of Anesthesia, Shenzhen People's Hospital, Shenzhen, Guangdong 5188020, P.R. China
| |
Collapse
|
|
42
|
Goto K, Arai J, Stephanou A, Kato N. Novel therapeutic features of disulfiram against hepatocellular carcinoma cells with inhibitory effects on a disintegrin and metalloproteinase 10. Oncotarget 2018; 9:18821-18831. [PMID: 29721164 PMCID: PMC5922358 DOI: 10.18632/oncotarget.24568] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 02/24/2018] [Indexed: 12/25/2022] Open
Abstract
Our previous genome-wide association study identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) as a susceptibility gene for hepatitis C virus-induced hepatocellular carcinoma (HCC). We subsequently proved that pharmacological restoration of membrane-bound MICA in HCC cells boosted natural killer cell-mediated anti-cancer effects, confirming that a MICA sheddase, a disintegrin and metalloproteinase 10 (ADAM10), is a therapeutic target. We here searched for approved drugs with inhibitory effects on ADAM10 in vitro, and the anti-alcoholism agent, disulfiram, was identified. Disulfiram elevated membrane-bound MICA levels and reduced production of soluble MICA, an immunological decoy, while simultaneously not having unfavorable off-target effects on natural killer cells and normal human hepatocytes. Functional analyses indicated a mode of non-zinc-binding inhibition of ADAM10 by disulfiram, which also suppressed HCC cell migration. These effects of disulfiram against HCC are expected to further the development of novel therapeutic regimens.
Collapse
Affiliation(s)
- Kaku Goto
- The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.,Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan
| | - Jun Arai
- The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.,Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo 142-8555, Japan
| | - Anthony Stephanou
- The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Naoya Kato
- The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.,Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| |
Collapse
|
|
43
|
Tan SK, Jermakowicz A, Mookhtiar AK, Nemeroff CB, Schürer SC, Ayad NG. Drug Repositioning in Glioblastoma: A Pathway Perspective. Front Pharmacol 2018; 9:218. [PMID: 29615902 PMCID: PMC5864870 DOI: 10.3389/fphar.2018.00218] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 02/27/2018] [Indexed: 12/27/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant primary adult brain tumor. The current standard of care is surgical resection, radiation, and chemotherapy treatment, which extends life in most cases. Unfortunately, tumor recurrence is nearly universal and patients with recurrent glioblastoma typically survive <1 year. Therefore, new therapies and therapeutic combinations need to be developed that can be quickly approved for use in patients. However, in order to gain approval, therapies need to be safe as well as effective. One possible means of attaining rapid approval is repurposing FDA approved compounds for GBM therapy. However, candidate compounds must be able to penetrate the blood-brain barrier (BBB) and therefore a selection process has to be implemented to identify such compounds that can eliminate GBM tumor expansion. We review here psychiatric and non-psychiatric compounds that may be effective in GBM, as well as potential drugs targeting cell death pathways. We also discuss the potential of data-driven computational approaches to identify compounds that induce cell death in GBM cells, enabled by large reference databases such as the Library of Integrated Network Cell Signatures (LINCS). Finally, we argue that identifying pathways dysregulated in GBM in a patient specific manner is essential for effective repurposing in GBM and other gliomas.
Collapse
Affiliation(s)
- Sze Kiat Tan
- Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, Miami Project to Cure Paralysis, Sylvester Comprehensive Cancer Center, University of Miami Brain Tumor Initiative, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Anna Jermakowicz
- Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, Miami Project to Cure Paralysis, Sylvester Comprehensive Cancer Center, University of Miami Brain Tumor Initiative, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Adnan K Mookhtiar
- Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, Miami Project to Cure Paralysis, Sylvester Comprehensive Cancer Center, University of Miami Brain Tumor Initiative, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Charles B Nemeroff
- Department of Psychiatry and Behavioral Sciences and Center on Aging, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Stephan C Schürer
- Department of Molecular Pharmacology, Center for Computational Sciences, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Nagi G Ayad
- Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, Miami Project to Cure Paralysis, Sylvester Comprehensive Cancer Center, University of Miami Brain Tumor Initiative, University of Miami Miller School of Medicine, Miami, FL, United States
| |
Collapse
|
|
44
|
Goto K, Kato N, Chung RT. Anti-hepatocellular carcinoma properties of the anti-alcoholism drug disulfiram discovered to enzymatically inhibit the AMPK-related kinase SNARK in vitro. Oncotarget 2018; 7:74987-74999. [PMID: 27602492 PMCID: PMC5342717 DOI: 10.18632/oncotarget.11820] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 08/24/2016] [Indexed: 11/25/2022] Open
Abstract
We recently described that the anti-apoptotic AMPK-related kinase, SNARK, promotes transforming growth factor (TGF)-β signaling in hepatocellular carcinoma (HCC) cells, as a potentially new therapeutic target. Here we explored FDA-approved drugs inhibiting the enzymatic activity of SNARK, using an in vitro luminescence kinase assay system. Interestingly, the long-used anti-alcoholism drug disulfiram (DSF), also known as Antabuse, emerged as the top hit. Enzymatic kinetics analyses revealed that DSF inhibited SNARK kinase activity in a noncompetitive manner to ATP or phosphosubstrates. Comparative in vitro analyses of DSF analogs indicated the significance of the disulfide bond-based molecular integrity for the kinase inhibition. DSF suppressed SNARK-promoted TGF-β signaling and demonstrated anti-HCC effects. The chemical and enzymatic findings herein reveal novel pharmacological effects of and use for DSF and its derivatives, and could be conducive to prevention and inhibition of liver fibrosis and HCC.
Collapse
Affiliation(s)
- Kaku Goto
- The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Naoya Kato
- The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| |
Collapse
|
|
45
|
Kengen J, Deglasse JP, Neveu MA, Mignion L, Desmet C, Gourgue F, Jonas JC, Gallez B, Jordan BF. Biomarkers of tumour redox status in response to modulations of glutathione and thioredoxin antioxidant pathways. Free Radic Res 2018; 52:256-266. [DOI: 10.1080/10715762.2018.1427236] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Julie Kengen
- Louvain Drug Research Institute, Biomedical Magnetic Resonance Group, Université Catholique de Louvain (UCL), Brussels, Belgium
| | - Jean-Philippe Deglasse
- Institute of Experimental and Clinical Research, Pole of Endocrinology, Diabetes and Nutrition, Université Catholique de Louvain, Brussels, Belgium
| | - Marie-Aline Neveu
- Louvain Drug Research Institute, Biomedical Magnetic Resonance Group, Université Catholique de Louvain (UCL), Brussels, Belgium
| | - Lionel Mignion
- Louvain Drug Research Institute, Biomedical Magnetic Resonance Group, Université Catholique de Louvain (UCL), Brussels, Belgium
| | - Céline Desmet
- Louvain Drug Research Institute, Biomedical Magnetic Resonance Group, Université Catholique de Louvain (UCL), Brussels, Belgium
| | - Florian Gourgue
- Louvain Drug Research Institute, Biomedical Magnetic Resonance Group, Université Catholique de Louvain (UCL), Brussels, Belgium
| | - Jean-Christophe Jonas
- Institute of Experimental and Clinical Research, Pole of Endocrinology, Diabetes and Nutrition, Université Catholique de Louvain, Brussels, Belgium
| | - Bernard Gallez
- Louvain Drug Research Institute, Biomedical Magnetic Resonance Group, Université Catholique de Louvain (UCL), Brussels, Belgium
| | - Bénédicte F. Jordan
- Louvain Drug Research Institute, Biomedical Magnetic Resonance Group, Université Catholique de Louvain (UCL), Brussels, Belgium
| |
Collapse
|
|
46
|
Zhao P, Wang Y, Kang X, Wu A, Yin W, Tang Y, Wang J, Zhang M, Duan Y, Huang Y. Dual-targeting biomimetic delivery for anti-glioma activity via remodeling the tumor microenvironment and directing macrophage-mediated immunotherapy. Chem Sci 2018; 9:2674-2689. [PMID: 29732051 PMCID: PMC5914428 DOI: 10.1039/c7sc04853j] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 01/29/2018] [Indexed: 12/18/2022] Open
Abstract
A dual-targeting biomimetic codelivery and treatment strategy was developed for anti-glioma activity.
Tumor-associated macrophages (TAMs) are the major components in the tumor microenvironment (TME). The polarization from the protumor M2 (TAM2) to antitumor M1 (TAM1) phenotype can not only lift the immunosuppressive constraints and elicit cytotoxic T-cell immunity but also augment the chemotherapy efficacy. However, the treatment feasibility by TAM modulation in brain tumors and the mechanisms remained unknown. A dual-targeting biomimetic codelivery and treatment strategy was developed for anti-glioma activity. We demonstrated that the albumin nanoparticles modified with dual ligands, a transferrin receptor (TfR)-binding peptide T12 and mannose, efficiently passed through the BBB via the nutrient transporters (i.e., TfR and the albumin-binding receptor SPARC) that were both overexpressed in the BBB and glioma cells, thus achieving biomimetic delivery to glioma. Importantly, after penetrating the BBB, this system can take advantage of the overexpression of the SPARC and mannose receptors on TAM2, thus also targeting the protumor TAM2. With the codelivery disulfiram/copper complex and regorafenib, the system efficiently inhibited the glioma cell proliferation and successfully “re-educated” the protumor TAM2 towards antitumor TAM1. The treatment efficacy was examined in the glioma-bearing nude mice and immunocompetent mice. It showed this system yielded an enhanced treatment outcome, owing to the synergistic combination of chemotherapy and macrophage-directed immunotherapy. The importance of this delivery and therapeutic strategy was to remodel the immune microenvironment and reprogram TAM and trigger macrophage-directed anti-glioma immunotherapy via the interplay of the TAM, Treg, and CD8+ T cells and the effector cytokines. The albumin-based biomimetic brain delivery also provides a promising method for the pharmacotherapy of brain diseases.
Collapse
Affiliation(s)
- Pengfei Zhao
- Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 501 Haike Rd , Shanghai 201203 , China . ; ; Tel: +86-21-2023-1981.,Zhejiang Academy of Medical Science , 182 Tianmushan Rd , Hangzhou 310013 , China.,Nanchang University College of Pharmacy , 461 Bayi Rd , Nanchang 330006 , China
| | - Yonghui Wang
- Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 501 Haike Rd , Shanghai 201203 , China . ; ; Tel: +86-21-2023-1981
| | - Xuejia Kang
- Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 501 Haike Rd , Shanghai 201203 , China . ; ; Tel: +86-21-2023-1981.,Guangzhou University of Chinese Medicine Tropical Medicine Institute , 12 Jichang Rd , Guangzhou 501450 , China
| | - Aihua Wu
- Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 501 Haike Rd , Shanghai 201203 , China . ; ; Tel: +86-21-2023-1981.,Guangzhou University of Chinese Medicine Tropical Medicine Institute , 12 Jichang Rd , Guangzhou 501450 , China
| | - Weimin Yin
- Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 501 Haike Rd , Shanghai 201203 , China . ; ; Tel: +86-21-2023-1981.,Nanchang University College of Pharmacy , 461 Bayi Rd , Nanchang 330006 , China
| | - Yisi Tang
- Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 501 Haike Rd , Shanghai 201203 , China . ; ; Tel: +86-21-2023-1981.,Guangzhou University of Chinese Medicine Tropical Medicine Institute , 12 Jichang Rd , Guangzhou 501450 , China
| | - Jinyu Wang
- Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 501 Haike Rd , Shanghai 201203 , China . ; ; Tel: +86-21-2023-1981
| | - Meng Zhang
- Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 501 Haike Rd , Shanghai 201203 , China . ; ; Tel: +86-21-2023-1981
| | - Yifei Duan
- Nanchang University College of Pharmacy , 461 Bayi Rd , Nanchang 330006 , China
| | - Yongzhuo Huang
- Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 501 Haike Rd , Shanghai 201203 , China . ; ; Tel: +86-21-2023-1981
| |
Collapse
|
|
47
|
Fernandez Del Ama L, Jones M, Walker P, Chapman A, Braun JA, Mohr J, Hurlstone AFL. Reprofiling using a zebrafish melanoma model reveals drugs cooperating with targeted therapeutics. Oncotarget 2018; 7:40348-40361. [PMID: 27248171 PMCID: PMC5130012 DOI: 10.18632/oncotarget.9613] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 05/04/2016] [Indexed: 12/23/2022] Open
Abstract
Phenotype-guided re-profiling of approved drug molecules presents an accelerated route to developing anticancer therapeutics by bypassing the target-identification bottleneck of target-based approaches and by sampling drugs already in the clinic. Further, combinations incorporating targeted therapies can be screened for both efficacy and toxicity. Previously we have developed an oncogenic-RAS-driven zebrafish melanoma model that we now describe display melanocyte hyperplasia while still embryos. Having devised a rapid method for quantifying melanocyte burden, we show that this phenotype can be chemically suppressed by incubating V12RAS transgenic embryos with potent and selective small molecule inhibitors of either MEK or PI3K/mTOR. Moreover, we demonstrate that combining MEK inhibitors (MEKi) with dual PI3K/mTOR inhibitors (PI3K/mTORi) resulted in a super-additive suppression of melanocyte hyperplasia. The robustness and simplicity of our novel screening assay inspired us to perform a modest screen of FDA approved compounds for their ability to potentiate MEKi PD184352 or PI3K/mTORi NVPBEZ235 suppression of V12RAS-driven melanocyte hyperplasia. Through this route, we confirmed Rapamycin as a compound that could synergize with MEKi and even more so with PI3K/mTORi to suppress melanoma development, including suppressing the growth of cultured human melanoma cells. Further, we discovered two additional compounds-Disulfiram and Tanshinone-that also co-operate with MEKi to suppress the growth of transformed zebrafish melanocytes and showed activity toward cultured human melanoma cells. In conclusion, we provide proof-of-concept that our phenotype-guided screen could be used to identify compounds that affect melanoma development and prompt further evaluation of Disulfiram and Tanshinone as possible partners for combination therapy.
Collapse
Affiliation(s)
| | - Mary Jones
- Faculty of Life Sciences, The University of Manchester, Manchester, UK
| | - Paul Walker
- Faculty of Life Sciences, The University of Manchester, Manchester, UK
| | - Anna Chapman
- Faculty of Life Sciences, The University of Manchester, Manchester, UK
| | - Julia A Braun
- Faculty of Life Sciences, The University of Manchester, Manchester, UK
| | - Jasmine Mohr
- Faculty of Life Sciences, The University of Manchester, Manchester, UK
| | | |
Collapse
|
|
48
|
Jivan R, Peres J, Damelin LH, Wadee R, Veale RB, Prince S, Mavri-Damelin D. Disulfiram with or without metformin inhibits oesophageal squamous cell carcinoma in vivo. Cancer Lett 2017; 417:1-10. [PMID: 29274360 DOI: 10.1016/j.canlet.2017.12.026] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 11/30/2017] [Accepted: 12/15/2017] [Indexed: 12/18/2022]
Abstract
Oesophageal squamous cell carcinoma (OSCC) is highly prevalent in developing countries but there has been little recent progress into efficacious yet affordable treatment strategies. Drug repurposing is one attractive approach for cancer therapy. Disulfiram (DSF), used to treat alcoholism, inhibits cancer growth and we previously found that DSF perturbs protein degradation/turnover pathways in vitro. This was enhanced by combining DSF with the anti-diabetic drug metformin (Met). Here, we investigated DSF with/without Met, against OSCC in vivo. Nude mice injected subcutaneously with the human OSCC cell line WHCO1, were treated with 30 mg/kg or 50 mg/kg DSF three times per week and with/without Met, for 21 days. DSF and DSF/Met-treated animals had significantly smaller tumours compared to untreated, vehicle and positive control cisplatin-treated groups. This effect for DSF was independent of copper, with no significant accumulation of copper in tumours, together with maintained proteasome activity. However, increases in total ubiquitinated proteins, LC3B-II, LAMP1 and p62 in DSF and DSF/Met groups, indicate that autophagy is inhibited. These findings show that DSF and DSF/Met significantly impede OSCC tumour growth in vivo and offer prospective alternative chemotherapy approaches for OSCC.
Collapse
Affiliation(s)
- Rupal Jivan
- The School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, Private Bag X3, WITS 2050, South Africa
| | - Jade Peres
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa
| | - Leonard Howard Damelin
- The School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa; Cell Biology Group, Centre for HIV and STI's, National Institute for Communicable Diseases (NHLS), Private Bag X4, Sandringham, Johannesburg 2131, South Africa
| | - Reubina Wadee
- Division of Anatomical Pathology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa
| | - Robin Bruce Veale
- The School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, Private Bag X3, WITS 2050, South Africa
| | - Sharon Prince
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa
| | - Demetra Mavri-Damelin
- The School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, Private Bag X3, WITS 2050, South Africa.
| |
Collapse
|
|
49
|
Dong Y, Furuta T, Sabit H, Kitabayashi T, Jiapaer S, Kobayashi M, Ino Y, Todo T, Teng L, Hirao A, Zhao SG, Nakada M. Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug. Oncotarget 2017; 8:111728-111741. [PMID: 29340087 PMCID: PMC5762355 DOI: 10.18632/oncotarget.22904] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 11/15/2017] [Indexed: 12/14/2022] Open
Abstract
Glioma stem cell (GSC)-targeted therapy is expected to be one of the most innovative approaches to treat patients with glioblastoma (GBM). A number of the drugs that restrain the signaling pathway essential for GSC maintenance have been under clinical trials. Here, we identified fluspirilene, a traditional antipsychotic drug, as a GSC-targeting agent, selected from thousands of existing drugs, and investigated its therapeutic effects against GBM with the purpose of drug repositioning. To develop novel therapeutics targeting GSCs, we initially screened drug libraries for small-molecule compounds showing a greater efficacy, compared to that of controls, in inhibiting the proliferation and survival of different GSC lines using cell proliferation assay. Drugs already reported to show therapeutic effects against GBM or those under clinical trials were excluded from subsequent screening. Finally, we found three drugs showing remarkable antiproliferative effects on GSCs at low concentrations and investigated their therapeutic effects on GSCs, glioma cell lines, and in a GBM mouse model. Of the three compounds, fluspirilene demonstrated a significant inhibitory effect on the proliferation and invasion of glioma cells as well as in the model mice treated with the drug. These effects were associated with the inactivation of the signal transducer and activator of transcription 3 (STAT3). Redeveloping of fluspirilene is a promising approach for the treatment of GBM.
Collapse
Affiliation(s)
- Yu Dong
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Takuya Furuta
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Hemragul Sabit
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Tomohiro Kitabayashi
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Shabierjiang Jiapaer
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Masahiko Kobayashi
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Yasushi Ino
- Laboratory of Innovative Cancer Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Tomoki Todo
- Laboratory of Innovative Cancer Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Lei Teng
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Atsushi Hirao
- Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Shi-Guang Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Mitsutoshi Nakada
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| |
Collapse
|
|
50
|
Abbruzzese C, Matteoni S, Signore M, Cardone L, Nath K, Glickson JD, Paggi MG. Drug repurposing for the treatment of glioblastoma multiforme. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:169. [PMID: 29179732 PMCID: PMC5704391 DOI: 10.1186/s13046-017-0642-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 11/17/2017] [Indexed: 01/07/2023]
Abstract
Background Glioblastoma Multiforme is the deadliest type of brain tumor and is characterized by very poor prognosis with a limited overall survival. Current optimal therapeutic approach has essentially remained unchanged for more than a decade, consisting in maximal surgical resection followed by radiotherapy plus temozolomide. Main body Such a dismal patient outcome represents a compelling need for innovative and effective therapeutic approaches. Given the development of new drugs is a process presently characterized by an immense increase in costs and development time, drug repositioning, finding new uses for existing approved drugs or drug repurposing, re-use of old drugs when novel molecular findings make them attractive again, are gaining significance in clinical pharmacology, since it allows faster and less expensive delivery of potentially useful drugs from the bench to the bedside. This is quite evident in glioblastoma, where a number of old drugs is now considered for clinical use, often in association with the first-line therapeutic intervention. Interestingly, most of these medications are, or have been, widely employed for decades in non-neoplastic pathologies without relevant side effects. Now, the refinement of their molecular mechanism(s) of action through up-to-date technologies is paving the way for their use in the therapeutic approach of glioblastoma as well as other cancer types. Short conclusion The spiraling costs of new antineoplastic drugs and the long time required for them to reach the market demands a profoundly different approach to keep lifesaving therapies affordable for cancer patients. In this context, repurposing can represent a relatively inexpensive, safe and fast approach to glioblastoma treatment. To this end, pros and cons must be accurately considered.
Collapse
Affiliation(s)
- Claudia Abbruzzese
- Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Cellular Networks and Therapeutic Targets, Proteomics Area, Regina Elena National Cancer Institute, IRCCS, Via Elio Chianesi, 53, Rome, Italy
| | - Silvia Matteoni
- Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Cellular Networks and Therapeutic Targets, Proteomics Area, Regina Elena National Cancer Institute, IRCCS, Via Elio Chianesi, 53, Rome, Italy
| | - Michele Signore
- RPPA Unit, Proteomics Area, Core Facilities, Istituto Superiore di Sanità, Rome, Italy
| | - Luca Cardone
- Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Cellular Networks and Therapeutic Targets, Regina Elena National Cancer Institute, IRCCS, Rome, Italy
| | - Kavindra Nath
- Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Jerry D Glickson
- Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Marco G Paggi
- Department of Research, Advanced Diagnostics and Technological Innovation, Unit of Cellular Networks and Therapeutic Targets, Proteomics Area, Regina Elena National Cancer Institute, IRCCS, Via Elio Chianesi, 53, Rome, Italy.
| |
Collapse
|