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Qian X, Liu Y, Chen W, Zheng S, Lu Y, Qiu P, Ke X, Tang H, Zhang X. Paris saponin VII induces Caspase-3/GSDME-dependent pyroptosis in pancreatic ductal adenocarcinoma cells by activating ROS/Bax signaling. CHINESE HERBAL MEDICINES 2025; 17:94-107. [PMID: 39949804 PMCID: PMC11814252 DOI: 10.1016/j.chmed.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 03/14/2024] [Accepted: 04/07/2024] [Indexed: 02/16/2025] Open
Abstract
Objective Paridis Rhizoma (Chonglou in Chinese), a traditional Chinese herbal medicine, has been shown have strong anti-tumor effects. Paris saponin VII (PSVII), an active constituent isolated from Paridis Rhizoma, was demonstrated to significantly suppress the proliferation of BxPC-3 cells in our previous study. Here, we aimed to elucidate the anti-pancreatic ductal adenocarcinoma (PDAC) effect of PSVII and the underlying mechanism. Methods Cell viability was determined by CCK-8, colony formation, and cell migration assays. Cell apoptosis and reactive oxygen species (ROS) production were measured by flow cytometry with annexin V/propidine iodide (Annexin V/PI) and 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), respectively. Pyroptosis was evaluated by morphological features, Hoechst 33342/PI staining assay, and release of lactate dehydrogenase (LDH). JC-1 fluorescent dye was employed to measure mitochondrial membrane potential. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to determine the levels of proteins or mRNAs. The effect in vivo was assessed by a xenograft tumor model. Results PSVII inhibited the viability of PDAC cells (BxPC-3, PANC-1, and Capan-2 cells) and induced gasdermin E (GSDME) cleavage, as well as the simultaneous cleavage of Caspase-3 and poly (ADP-ribose) polymerase 1 (PARP). Knockdown of GSDME shifted PSVII-induced pyroptosis to apoptosis. Additionally, the effect of PSVII was significantly attenuated by Z-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone (Z-DEVD-FMK), on the induction of GSDME-dependent pyroptosis. PSVII also elevated intracellular ROS accumulation and stimulated Bax and Caspase-3/GSDME to conduct pyroptosis in PDAC cells. The ROS scavenger N-acetyl cysteine (NAC) suppressed the release of LDH and inhibited Caspase-9, Caspase-3, and GSDME cleavage in PDAC cells, ultimately reversing PSVII-induced pyroptosis. Furthermore, in a xenograft tumor model, PSVII markedly suppressed the growth of PDAC tumors and induced pyroptosis. Conclusion These results demonstrated that PSVII exerts therapeutic effects through Caspase-3/GSDME-dependent pyroptosis and may constitute a novel strategy for preventing chemotherapeutic resistance in patients with PDAC in the future.
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Affiliation(s)
- Xiaoying Qian
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi’an 710032, China
| | - Yang Liu
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi’an 710032, China
| | - Wenwen Chen
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi’an 710032, China
| | - Shuxian Zheng
- School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Yunyang Lu
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi’an 710032, China
| | - Pengcheng Qiu
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi’an 710032, China
| | - Xisong Ke
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Haifeng Tang
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi’an 710032, China
| | - Xue Zhang
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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2
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Xu Q, Kowalski J. Non-B DNA-informed mutation burden as a marker of treatment response and outcome in cancer. Br J Cancer 2024; 131:1825-1832. [PMID: 39427051 PMCID: PMC11589871 DOI: 10.1038/s41416-024-02873-7] [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: 03/26/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Genomic instability is crucial in tumorigenesis, with Tumour Mutation Burden (TMB) being a biomarker to indicate therapeutic effectiveness, particularly in immunotherapy. However, TMB is not always a reliable predictor and displays heterogeneity. Non-B DNA, susceptible to mutations, play a significant role in cancer development, indicating their potential merit when combined with mutation for enhanced markers in cancer. METHODS We assessed mutations and non-B DNA interplay as biomarkers. Our methodology quantifies tumour mutations and their co-localization with non-B DNA, using survival and drug sensitivity assessments for clinical relevance. RESULTS We introduce two novel markers, 'nbTMB' (non-B-informed tumour mutation burden) and 'mlTNB' (mutation-localised tumour non-B burden). In case studies: (1) nbTMB informs on survival heterogeneity among TMB-high patients undergoing immunotherapy whereas TMB is unable to further differentiate; (2) nbTMB informs on altered cisplatin sensitivity among ovarian cancer cell lines whereas TMB is unable to differentiate; and (3) mlTNB informs on survival heterogeneity among early-stage pancreatic cancer progressors in whom other markers of genomic instability fail to differentiate. CONCLUSIONS These novel markers offer a nuanced approach to enhance our understanding of treatment responses and outcomes in cancer, underscoring the need for a comprehensive exploration of the interplay between non-B and B-DNA features.
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Affiliation(s)
- Qi Xu
- Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
- Department of Molecular Biosciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX, USA
| | - Jeanne Kowalski
- Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
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3
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Ha Y, Kang W, Roh J, Jung Y, Lee H, Park T. Acetyl tributyl citrate attenuates 5-fluorouracil-induced inflammation, oxidative stress, and apoptosis in human keratinocytes. Biochem Pharmacol 2024; 230:116606. [PMID: 39489222 DOI: 10.1016/j.bcp.2024.116606] [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: 07/09/2024] [Revised: 10/15/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024]
Abstract
5-Fluorouracil (5-FU) is a commonly used chemotherapy drug that effectively destroys cancer cells. Despite its widespread use and efficacy, it also presents considerable challenges, particularly with adverse effects on rapidly dividing normal cells, such as keratinocytes. These detrimental effects are attributed to inflammatory, oxidative, and apoptotic potentials, leading to severe skin disorders. Due to the lack of specific remedies for 5-FU-induced dermatological side effects, conventional treatments are applied instead, which provide limited relief and have drawbacks. This study investigated the impact of acetyl tributyl citrate (ATBC) in 5-FU-treated human keratinocytes. The findings indicated that ATBC substantially reduced inflammation caused by 5-FU, as demonstrated by nuclear translocation of nuclear factor kappa B and expression of its downstream genes, including tumor necrosis factor, interleukin 1 beta (IL1B), and IL6. ATBC also markedly decreased oxidative stress, indicated by reactive oxygen species levels and the antioxidant gene expression such as superoxide dismutase 1 (SOD1), SOD2, and heme oxygenase 1 in 5-FU-treated cells. Furthermore, ATBC attenuated 5-FU-induced apoptosis, as determined by lactate dehydrogenase release and Annexin V/propidium iodide flow cytometry, with the potential involvement of interferon-related genes. Following this, protein kinase C delta was predicted as a possible molecular target of ATBC. These findings propose ATBC as a therapeutic agent for managing the cutaneous side effects associated with 5-FU treatment.
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Affiliation(s)
- Yoojeong Ha
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Wesuk Kang
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Jiyun Roh
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Yearim Jung
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Hyunbin Lee
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Taesun Park
- Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
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Kookli K, Soleimani KT, Amr EF, Ehymayed HM, Zabibah RS, Daminova SB, Saadh MJ, Alsaikhan F, Adil M, Ali MS, Mohtashami S, Akhavan-Sigari R. Role of microRNA-146a in cancer development by regulating apoptosis. Pathol Res Pract 2024; 254:155050. [PMID: 38199132 DOI: 10.1016/j.prp.2023.155050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 01/12/2024]
Abstract
Despite great advances in diagnostic and treatment options for cancer, like chemotherapy surgery, and radiation therapy it continues to remain a major global health concern. Further research is necessary to find new biomarkers and possible treatment methods for cancer. MicroRNAs (miRNAs), tiny non-coding RNAs found naturally in the body, can influence the activity of several target genes. These genes are often disturbed in diseases like cancer, which perturbs functions like differentiation, cell division, cell cycle, apoptosis and proliferation. MiR-146a is a commonly and widely used miRNA that is often overexpressed in malignant tumors. The expression of miR-146a has been correlated with many pathological and physiological changes in cancer cells, such as the regulation of various cell death paths. It's been established that the control of cell death pathways has a huge influence on cancer progression. To improve our understanding of the interrelationship between miRNAs and cancer cell apoptosis, it's necessary to explore the impact of miRNAs through the alteration in their expression levels. Research has demonstrated that the appearance and spread of cancer can be mitigated by moderating the expression of certain miRNA - a commencement of treatment that presents a hopeful approach in managing cancer. Consequently, it is essential to explore the implications of miR-146a with respect to inducing different forms of tumor cell death, and evaluate its potential to serve as a target for improved chemotherapy outcomes. Through this review, we provide an outline of miR-146a's biogenesis and function, as well as its significant involvement in apoptosis. As well, we investigate the effects of exosomal miR-146a on the promotion of apoptosis in cancer cells and look into how it could possibly help combat chemotherapeutic resistance.
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Affiliation(s)
- Keihan Kookli
- International Campus, Iran University of Medical Sciences, Tehran, Iran
| | | | - Eman Fathy Amr
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Shakhnoza B Daminova
- Department of Prevention of Dental Diseases, Tashkent State Dental Institute, Tashkent, Uzbekistan; Department of Scientific affairs, Tashkent Medical Pediatric Institute, Bogishamol Street 223, Tashkent, Uzbekistan
| | - Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia; School of Pharmacy, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
| | | | | | - Saghar Mohtashami
- University of California Los Angeles, School of Dentistry, Los Angeles, CA, USA.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University Warsaw, Poland
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5
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Zarrabi A, Perrin D, Kavoosi M, Sommer M, Sezen S, Mehrbod P, Bhushan B, Machaj F, Rosik J, Kawalec P, Afifi S, Bolandi SM, Koleini P, Taheri M, Madrakian T, Łos MJ, Lindsey B, Cakir N, Zarepour A, Hushmandi K, Fallah A, Koc B, Khosravi A, Ahmadi M, Logue S, Orive G, Pecic S, Gordon JW, Ghavami S. Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies. Cancers (Basel) 2023; 15:5269. [PMID: 37958442 PMCID: PMC10650215 DOI: 10.3390/cancers15215269] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 10/18/2023] [Accepted: 10/29/2023] [Indexed: 11/15/2023] Open
Abstract
Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.
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Affiliation(s)
- Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer, Istanbul 34396, Türkiye; (A.Z.); (A.Z.)
| | - David Perrin
- Section of Orthopaedic Surgery, Department of Surgery, University of Manitoba, Winnipeg, MB R3E 0V9, Canada; (D.P.); (M.S.)
| | - Mahboubeh Kavoosi
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
- Biotechnology Center, Silesian University of Technology, 8 Krzywousty St., 44-100 Gliwice, Poland;
| | - Micah Sommer
- Section of Orthopaedic Surgery, Department of Surgery, University of Manitoba, Winnipeg, MB R3E 0V9, Canada; (D.P.); (M.S.)
- Section of Physical Medicine and Rehabilitation, Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Serap Sezen
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul 34956, Türkiye; (S.S.); (N.C.); (B.K.)
| | - Parvaneh Mehrbod
- Department of Influenza and Respiratory Viruses, Pasteur Institute of Iran, Tehran 1316943551, Iran;
| | - Bhavya Bhushan
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
- Department of Anatomy and Cell Biology, School of Biomedical Sciences, Faculty of Science, McGill University, Montreal, QC H3A 0C7, Canada
| | - Filip Machaj
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA
| | - Jakub Rosik
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland
- Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
| | - Philip Kawalec
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
- Section of Neurosurgery, Department of Surgery, University of Manitoba, Health Sciences Centre, Winnipeg, MB R3A 1R9, Canada
| | - Saba Afifi
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
| | - Seyed Mohammadreza Bolandi
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
| | - Peiman Koleini
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
| | - Mohsen Taheri
- Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran;
| | - Tayyebeh Madrakian
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838695, Iran; (T.M.); (M.A.)
| | - Marek J. Łos
- Biotechnology Center, Silesian University of Technology, 8 Krzywousty St., 44-100 Gliwice, Poland;
| | - Benjamin Lindsey
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
| | - Nilufer Cakir
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul 34956, Türkiye; (S.S.); (N.C.); (B.K.)
| | - Atefeh Zarepour
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer, Istanbul 34396, Türkiye; (A.Z.); (A.Z.)
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran 1419963114, Iran;
| | - Ali Fallah
- Integrated Manufacturing Technologies Research and Application Center, Sabanci University, Tuzla, Istanbul 34956, Türkiye;
| | - Bahattin Koc
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul 34956, Türkiye; (S.S.); (N.C.); (B.K.)
- Integrated Manufacturing Technologies Research and Application Center, Sabanci University, Tuzla, Istanbul 34956, Türkiye;
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Türkiye
| | - Arezoo Khosravi
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul 34959, Türkiye;
| | - Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838695, Iran; (T.M.); (M.A.)
| | - Susan Logue
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
| | - Gorka Orive
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), 01007 Vitoria-Gasteiz, Spain;
- University Institute for Regenerative Medicine and Oral Implantology–UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria-Gasteiz, Spain
- Bioaraba, NanoBioCel Research Group, 01006 Vitoria-Gasteiz, Spain
| | - Stevan Pecic
- Department of Chemistry and Biochemistry, California State University Fullerton, Fullerton, CA 92831, USA;
| | - Joseph W. Gordon
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
- College of Nursing, Rady Faculty of Health Science, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 0V9, Canada; (M.K.); (B.B.); (F.M.); (J.R.); (P.K.); (S.A.); (S.M.B.); (P.K.); (B.L.); (S.L.); (J.W.G.)
- Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
- Academy of Silesia, Faculty of Medicine, Rolna 43, 40-555 Katowice, Poland
- Research Institutes of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, MB R3E 0V9, Canada
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Jeong SD, Jung BK, Lee D, Ha J, Chang HG, Lee J, Lee S, Yun CO, Kim YC. Enhanced Immunogenic Cell Death by Apoptosis/Ferroptosis Hybrid Pathway Potentiates PD-L1 Blockade Cancer Immunotherapy. ACS Biomater Sci Eng 2022; 8:5188-5198. [PMID: 36449494 DOI: 10.1021/acsbiomaterials.2c00950] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
Even though chemotherapy regimens for treating cancer by inducing apoptosis are extensively utilized, their therapeutic effect is hindered by multiple limitations. Thus, a combination of other types of anticancer modalities is urgently needed. Herein, a tannic acid (TA)-Fe3+-coated doxorubicin (DOX)-encapsulated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (ammonium salt) (DSPE-PEG) micelle (TFDD) for apoptosis/ferroptosis-mediated immunogenic cell death (ICD) is reported. By coating TA-Fe3+ on the surface of DOX-loaded micelles, an apoptotic agent and a ferroptotic agent are simultaneously delivered into the cancer cells and induce cell death. Furthermore, the intracellular oxidative environment generated by the apoptosis/ferroptosis hybrid pathway stimulates the endoplasmic reticulum (ER) and leads to ICD induction. The in vivo results show that the combination treatment of TFDD and anti-programmed death-ligand 1 antibodies (anti-PD-L1) considerably inhibits tumor growth and improves antitumor immunity by activating CD4+ and CD8+ T cells and decreasing the ratio of regulatory T cells (Treg) to CD4+ T cells. This study suggests that the apoptosis/ferroptosis-mediated ICD inducer may offer a potent strategy for enhanced cancer immunotherapy.
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Affiliation(s)
- Seong Dong Jeong
- Department of Chemical and Biomolecular engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Bo-Kyeong Jung
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.,GeneMedicine, Co., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea
| | - DaeYong Lee
- Department of Chemical and Biomolecular engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.,Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
| | - JongHoon Ha
- Department of Chemical and Biomolecular engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Han-Gyu Chang
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea
| | - Jeongmin Lee
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea
| | - Susam Lee
- Department of Chemical and Biomolecular engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Chae-Ok Yun
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.,GeneMedicine, Co., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.,Institute of Nano Science and Technology (INST), Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea
| | - Yeu-Chun Kim
- Department of Chemical and Biomolecular engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
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7
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Romito O, Guéguinou M, Raoul W, Champion O, Robert A, Trebak M, Goupille C, Potier-Cartereau M. Calcium signaling: A therapeutic target to overcome resistance to therapies in cancer. Cell Calcium 2022; 108:102673. [PMID: 36410063 DOI: 10.1016/j.ceca.2022.102673] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/08/2022] [Accepted: 11/09/2022] [Indexed: 11/13/2022]
Abstract
Innate and acquired resistances to therapeutic agents are responsible for the failure of cancer treatments. Due to the multifactorial nature of resistance, the identification of new therapeutic targets is required to improve cancer treatment. Calcium is a universal second messenger that regulates many cellular functions such as proliferation, migration, and survival. Calcium channels, pumps and exchangers tightly regulate the duration, location and magnitude of calcium signals. Many studies have implicated dysregulation of calcium signaling in several pathologies, including cancer. Abnormal calcium fluxes due to altered channel expression or activation contribute to carcinogenesis and promote tumor development. However, there is limited information on the role of calcium signaling in cancer resistance to therapeutic drugs. This review discusses the role of calcium signaling as a mediator of cancer resistance, and assesses the potential value of combining anticancer therapy with calcium signaling modulators to improve the effectiveness of current treatments.
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Affiliation(s)
- Olivier Romito
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
| | - Maxime Guéguinou
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
| | - William Raoul
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
| | - Ophélie Champion
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
| | - Alison Robert
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
| | - Mohamed Trebak
- Vascular Medicine Institute, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Caroline Goupille
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France; CHRU de Tours, hôpital Bretonneau, Tours, France.
| | - Marie Potier-Cartereau
- Inserm UMR 1069, Nutrition Croissance Cancer, Faculté de Médecine, Université de Tours, F-37032, France, Réseau 3MC « Molécules Marines, Métabolisme et Cancer » and Réseau CASTOR «Cancers des Tissus Hormono-Dépendants » Cancéropôle Grand Ouest, France.
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Gambogic Acid Induces Pyroptosis of Colorectal Cancer Cells through the GSDME-Dependent Pathway and Elicits an Antitumor Immune Response. Cancers (Basel) 2022; 14:cancers14225505. [PMID: 36428598 PMCID: PMC9688471 DOI: 10.3390/cancers14225505] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/28/2022] [Accepted: 11/03/2022] [Indexed: 11/12/2022] Open
Abstract
Pyroptosis is a recently identified form of programmed cell death (PCD) that exerts a vital influence on the antitumor immune response. GA, a xanthone structure isolated from gamboge resin, is a naturally occurring bioactive ingredient with several anticancer activities, such as activities that affect cell cycle arrest, apoptosis, and autophagy. Here, we found that GA decreased the viability of the CRC cell lines, HCT116 and CT26, in a dose- and time-dependent manner, and multiple pores and large bubbles in the membranes, which are morphological characteristics of pyroptosis, were observed by light microscopy and transmission electron microscopy (TEM). Furthermore, the cleavage of gasdermin E (GSDME) was observed after exposure to GA, along with concomitant activation of caspase-3. Additionally, GSDME-dependent pyroptosis triggered by GA could be attenuated by siRNA-mediated knockdown of GSDME and treatment with the caspase-3 inhibitor. Moreover, we found that GA induced pyroptosis and significantly inhibited tumor growth in CT26 tumor-bearing mice. Strikingly, significantly increased proportions of CD3+ T cells, cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs) were observed in the tumor microenvironment in the GA-treated groups. Moreover, significantly increased proportions of CTLs and effector memory T cells (TEM) (CD8+ CD44+ CD62L-) were also detected in the spleens of the GA-treated groups, suggesting that the pyroptosis-induced immune response generated a robust memory response that mediated protective immunity. In this study, we revealed a previously unrecognized mechanism by which GA induces GSDME-dependent pyroptosis and enhances the anticancer immune response. Based on this mechanism, GA is a promising antitumor drug for CRC treatment that induces caspase-3-GSDME-dependent pyroptosis. This study provides novel insight into cancer chemoimmunotherapy.
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Ning YM, Lin K, Liu XP, Ding Y, Jiang X, Zhang Z, Xuan YT, Dong L, Liu L, Wang F, Zhao Q, Wang HZ, Fang J. NAPSB as a predictive marker for prognosis and therapy associated with an immuno-hot tumor microenvironment in hepatocellular carcinoma. BMC Gastroenterol 2022; 22:392. [PMID: 35987606 PMCID: PMC9392949 DOI: 10.1186/s12876-022-02475-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 08/04/2022] [Indexed: 11/29/2022] Open
Abstract
Background Napsin B Aspartic Peptidase, Pseudogene (NAPSB) was associated with CD4 + T cell infiltration in pancreatic ductal adenocarcinoma. However, the biological role of NAPSB in hepatocellular carcinoma (HCC) remains to be determined. Methods The expression of NAPSB in HCC as well as its clinicopathological association were analyzed using data from several public datasets. qRT-PCR was used to verify the relative expression of NAPSB in patients with HCC using the Zhongnan cohort. Kaplan–Meier analyses, and univariate and multivariate Cox regression were conducted to determine the prognosis value of NAPSB on patients with HCC. Then enrichment analyses were performed to identify the possible biological functions of NAPSB. Subsequently, the immunological characteristics of NAPSB in the HCC tumor microenvironment (TME) were demonstrated comprehensively. The role of NAPSB in predicting hot tumors and its impact on immunotherapy and chemotherapy responses was also analyzed by bioinformatics methods. Results NAPSB was downregulated in patients with HCC and high NAPSB expression showed an improved survival outcome. Enrichment analyses showed that NAPSB was related to immune activation. NAPSB was positively correlated with immunomodulators, tumor-infiltrating immune cells, T cell inflamed score and cancer-immunity cycle, and highly expressed in immuno-hot tumors. High expression of NAPSB was sensitive to immunotherapy and chemotherapy, possibly due to its association with pyroptosis, apoptosis and necrosis. Conclusions NAPSB was correlated with an immuno-hot and inflamed TME, and tumor cell death. It can be utilized as a promising predictive marker for prognosis and therapy in HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02475-8.
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10
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Boyenle ID, Oyedele AK, Ogunlana AT, Adeyemo AF, Oyelere FS, Akinola OB, Adelusi TI, Ehigie LO, Ehigie AF. Targeting the mitochondrial permeability transition pore for drug discovery: Challenges and opportunities. Mitochondrion 2022; 63:57-71. [PMID: 35077882 DOI: 10.1016/j.mito.2022.01.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/22/2021] [Accepted: 01/17/2022] [Indexed: 12/29/2022]
Abstract
Several drug targets have been amenable to drug discovery pursuit not until the characterization of the mitochondrial permeability transition pore (MPTP), a pore with an undefined molecular identity that forms on the inner mitochondrial membrane upon mitochondrial permeability transition (MPT) under the influence of calcium overload and oxidative stress. The opening of the pore which is presumed to cause cell death in certain human diseases also has implications under physiological parlance. Different models for this pore have been postulated following its first identification in the last six decades. The mitochondrial community has witnessed many protein candidates such as; voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), Mitochondrial phosphate carrier (PiC), Spastic Paralegin (SPG7), disordered proteins, and F1Fo ATPase. However, genetic studies have cast out most of these candidates with only F1Fo ATPase currently under intense argument. Cyclophilin D (CyPD) remains the widely accepted positive regulator of the MPTP known to date, but no drug candidate has emerged as its inhibitor, raising concern issues for therapeutics. Thus, in this review, we discuss various models of MPTP reported with the hope of stimulating further research in this field. We went beyond the classical description of the MPTP to ascribe a 'two-edged sword property' to the pore for therapeutic function in human disease because its inhibition and activation have pharmacological relevance. We suggested putative proteins upstream to CyPD that can regulate its activity and prevent cell deaths in neurodegenerative disease and ischemia-reperfusion injury.
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Affiliation(s)
- Ibrahim Damilare Boyenle
- Membrane Biochemistry and Biophysics Research Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria; Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Abdulquddus Kehinde Oyedele
- Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Abdeen Tunde Ogunlana
- Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Aishat Folashade Adeyemo
- Membrane Biochemistry and Biophysics Research Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | | | - Olateju Balikis Akinola
- Membrane Biochemistry and Biophysics Research Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Temitope Isaac Adelusi
- Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Leonard Ona Ehigie
- Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Adeola Folasade Ehigie
- Membrane Biochemistry and Biophysics Research Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria.
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11
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Darweesh O, Al-Shehri E, Falquez H, Lauterwasser J, Edlich F, Patel R. Identification of a novel Bax-Cdk1 signalling complex that links activation of the mitotic checkpoint to apoptosis. J Cell Sci 2021; 134:237811. [PMID: 33722980 DOI: 10.1242/jcs.244152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 02/16/2021] [Indexed: 11/20/2022] Open
Abstract
In eukaryotes, entry into and exit from mitosis is regulated, respectively, by the transient activation and inactivation of Cdk1. Taxol, an anti-microtubule anti-cancer drug, prevents microtubule-kinetochore attachments to induce spindle assembly checkpoint (SAC; also known as the mitotic checkpoint)-activated mitotic arrest. SAC activation causes mitotic arrest by chronically activating Cdk1. One consequence of prolonged Cdk1 activation is cell death. However, the cytoplasmic signal(s) that link SAC activation to the initiation of cell death remain unknown. We show here that activated Cdk1 forms a complex with the pro-apoptotic proteins Bax and Bak (also known as BAK1) during SAC-induced apoptosis. Bax- and Bak-mediated delivery of activated Cdk1 to the mitochondrion is essential for the phosphorylation of the anti-apoptotic proteins Bcl-2 and Bcl-xL (encoded by BCL2L1) and the induction of cell death. The interactions between a key cell cycle control protein and key pro-apoptotic proteins identify the Cdk1-Bax and Cdk1-Bak complexes as the long-sought-after cytoplasmic signal that couples SAC activation to the induction of apoptotic cell death.
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Affiliation(s)
- Omeed Darweesh
- Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH,UK
| | - Eman Al-Shehri
- Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH,UK
| | - Hugo Falquez
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Joachim Lauterwasser
- Veterinary Physiology-Chemistry Institute, University of Leipzig, An den Tierkliniken 1, 04103 Leipzig, Germany
| | - Frank Edlich
- Veterinary Physiology-Chemistry Institute, University of Leipzig, An den Tierkliniken 1, 04103 Leipzig, Germany
| | - Rajnikant Patel
- Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH,UK
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12
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Du Z, Li G, Ge H, Zhou X, Zhang J. Design, Synthesis and Biological Evaluation of Steroidal Glycoconjugates as Potential Antiproliferative Agents. ChemMedChem 2021; 16:1488-1498. [PMID: 33476082 DOI: 10.1002/cmdc.202000966] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/19/2021] [Indexed: 01/06/2023]
Abstract
To systematically evaluate the impact of neoglycosylation upon the anticancer activities and selectivity of steroids, four series of neoglycosides of diosgenin, pregnenolone, dehydroepiandrosterone and estrone were designed and synthesized according to the neoglycosylation approach. The structures of all the products were elucidated by NMR analysis, and the stereochemistry of C20-MeON-pregnenolone was confirmed by crystal X-ray diffraction. The compounds' cytotoxicity on five human cancer cell lines was evaluated using a Cell Counting Kit-8 assay, and structure-activity relationships (SAR) are discussed. 2-deoxy-d-glucoside 5 k displayed the most potent antiproliferative activities against HepG2 cells with an IC50 value of 1.5 μM. Further pharmacological experiments on compound 5 k on HepG2 cells revealed that it could cause morphological changes and cell-cycle arrest at the G0/G1 phase and then induced the apoptosis, which might be associated with the enhanced expression of high-mobility group Box 1 (HMGB1). Taken together, these findings prove that the neoglycosylation of steroids could be a promising strategy for the discovery of potential antiproliferative agents.
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Affiliation(s)
- Zhichao Du
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 210009, P. R. China
| | - Guolong Li
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, 211198, P. R. China
| | - Haixia Ge
- School of Life Sciences, Huzhou University, Huzhou, Zhejiang, 313000, P. R. China
| | - Xiaoyang Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 210009, P. R. China
| | - Jian Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 210009, P. R. China.,ZhenPing Expert Workstation for Zhang Jian Zhenping, Ankang, Shaanxi, 725699, P. R. China
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13
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Du Z, Li G, Zhou X, Zhang J. Synthesis of MeON-Glycoside Derivatives of Oleanolic Acid by Neoglycosylation and Evaluation of Their Cytotoxicity Against Selected Cancer Cell Lines. Molecules 2021; 26:molecules26030772. [PMID: 33540945 PMCID: PMC7867353 DOI: 10.3390/molecules26030772] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 11/16/2022] Open
Abstract
A series of C-3 and C-28 MeON-neoglycosides of oleanolic acid were designed and synthesized by neoglycosylation as potential antiproliferative agents. Their cytotoxicity was evaluated in vitro against five human cancer cell lines: human non-small cell lung cancer cell line (A549), human melanoma cell line (A375), human colon cancer cell line (HCT116), human liver carcinoma cell line (HepG2), human breast adenocarcinoma cell line (MCF-7) by the Cell Counting Kit-8 (CCK-8) assay. Most of C-3 and C-28 MeON-neoglycosides of oleanolic acid exhibited notably inhibitory effects against the tested cancer cells and more sensitive to HepG2 cells than 5-Fluorouracil (5-FU). Structure-activities relationship (SAR) analysis revealed that sugar types and the d/l configuration of sugars would significantly affect their antiproliferative activities of neoglycosides. Among them, compound 8a (28-N-methoxyaminooleanane-β-d-glucoside) exhibited the most potent antiproliferative activities against HepG2 cells with IC50 values of 2.1 µM. Further pharmacological experiments revealed that compound 8a could cause morphological changes and cell cycle arrest at G0/G1 phase and induce apoptosis in HepG2 cells. These results suggested that neoglycosylation could provide a rapid strategy for the discovery of potential antiproliferative agents and their possible pharmacological mechanisms need more further research.
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Affiliation(s)
- Zhichao Du
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China; (Z.D.); (X.Z.)
| | - Guolong Li
- Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, Jiangsu, China;
| | - Xiaoyang Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China; (Z.D.); (X.Z.)
| | - Jian Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China; (Z.D.); (X.Z.)
- Zhenping Expert Workstation for Zhang Jian, Zhenping, Ankang 725699, Shaanxi, China
- Correspondence: ; Tel.: +86-25-86185157
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14
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Fan D, Yang H, Mao W, Rask PJ, Pang L, Xu C, Vankayalapat H, Ahmed AA, Bast RC, Lu Z. A Novel Salt Inducible Kinase 2 Inhibitor, ARN-3261, Sensitizes Ovarian Cancer Cell Lines and Xenografts to Carboplatin. Cancers (Basel) 2021; 13:cancers13030446. [PMID: 33503955 PMCID: PMC7865895 DOI: 10.3390/cancers13030446] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 01/22/2021] [Indexed: 11/16/2022] Open
Abstract
Salt-induced kinase 2 (SIK2) is a serine-threonine kinase that regulates centrosome splitting, activation of PI3 kinase and phosphorylation of class IIa HDACs, affecting gene expression. Previously, we found that inhibition of SIK2 enhanced sensitivity of ovarian cancer cells to paclitaxel. Carboplatin and paclitaxel constitute first-line therapy for most patients with ovarian carcinoma, producing a 70% clinical response rate, but curing <20% of patients with advanced disease. We have asked whether inhibition of SIK2 with ARN-3261 enhances sensitivity to carboplatin in ovarian cancer cell lines and xenograft models. ARN-3261-induced DNA damage and apoptosis were measured with γ-H2AX accumulation, comet assays, and annexin V. ARN-3261 inhibited growth of eight ovarian cancer cell lines at an IC50 of 0.8 to 3.5 µM. ARN-3261 significantly enhanced sensitivity to carboplatin in seven of eight ovarian cancer cell lines and a carboplatin-resistant cell line tested. Furthermore, ARN-3261 in combination with carboplatin produced greater inhibition of tumor growth than carboplatin alone in SKOv3 and OVCAR8 ovarian cancer xenograft models. ARN-3261 enhanced DNA damage and apoptosis by downregulating expression of survivin. Thus, a SIK2 kinase inhibitor enhanced carboplatin-induced therapy in preclinical models of ovarian cancer and deserves further evaluation in clinical trials.
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Affiliation(s)
- Dengxuan Fan
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA; (D.F.); (H.Y.); (W.M.); (P.J.R.); (L.P.)
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China;
- Department of Obstetrics and Gynecology of Shanghai Medical College, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200011, China
| | - Hailing Yang
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA; (D.F.); (H.Y.); (W.M.); (P.J.R.); (L.P.)
| | - Weiqun Mao
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA; (D.F.); (H.Y.); (W.M.); (P.J.R.); (L.P.)
| | - Philip J. Rask
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA; (D.F.); (H.Y.); (W.M.); (P.J.R.); (L.P.)
| | - Lan Pang
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA; (D.F.); (H.Y.); (W.M.); (P.J.R.); (L.P.)
| | - Congjian Xu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China;
- Department of Obstetrics and Gynecology of Shanghai Medical College, Fudan University, Shanghai 200011, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200011, China
| | | | - Ahmed A. Ahmed
- The Nuffield Department of Obstetrics and Gynecology, University of Oxford, Oxford OX3 9DU, UK;
- Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, UK
| | - Robert C. Bast
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA; (D.F.); (H.Y.); (W.M.); (P.J.R.); (L.P.)
- Correspondence: (R.C.B.J.); (Z.L.); Tel.: +1-713-792-7743 (R.C.B.J. & Z.L.); Fax: +1-713-792-7864 (R.C.B.J. & Z.L.)
| | - Zhen Lu
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA; (D.F.); (H.Y.); (W.M.); (P.J.R.); (L.P.)
- Correspondence: (R.C.B.J.); (Z.L.); Tel.: +1-713-792-7743 (R.C.B.J. & Z.L.); Fax: +1-713-792-7864 (R.C.B.J. & Z.L.)
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Sutiningsih D, Ginandjar P, Dian Saraswati L, Mubarika Haryana S. Anticancer Activity of Pasak Bumi Root Extract ( Eurycoma longifolia Jack) on Raji Cells. Pak J Biol Sci 2021; 24:1226-1235. [PMID: 34989200 DOI: 10.3923/pjbs.2021.1226.1235] [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] [Indexed: 06/14/2023]
Abstract
<b>Background and Objective:</b> The use of the roots of the pasak bumi (<i>E. longifolia</i> Jack) to treat cancer has been studied widely, however, the scientific basis of these plants used as an anticancer drug is widely unknown. The purpose of this study was to examine the anticancer activity of ethyl acetate and non-ethyl acetate fractions of pasak bumi roots in Raji cells. <b>Materials and Methods:</b> The cytotoxicity test is using the direct cell count method with trypan blue staining. The growth inhibition is using doubling time analysis of Raji cells. Observation of the apoptotic events of Raji cells used ethidium bromide staining, while observing the expression of p53 protein in Raji cells was done by immunohistochemical staining. <b>Results:</b> The results of the cytotoxicity and doubling time test showed that the activity of the non-ethyl acetate fraction was greater than that of the roots of pasak bumi. The lower concentration of non-ethyl acetate fraction of pasak bumi roots was able to delay the multiplication time of Raji cells which was greater than that of ethyl acetate. The results of the cytotoxicity and doubling time test showed that the activity of the non-ethyl acetate fraction was greater than that of the roots of pasak bumi. <b>Conclusion:</b> It can be concluded that the ethyl acetate and non-ethyl acetate fractions of the roots of pasak bumi have cytotoxic and antiproliferative activity on Raji cells, however they cannot induce apoptosis in Raji cells. The death of Raji cells is through the mechanism of inhibiting Raji cell proliferation as evidenced by an increase in p53 protein expression.
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Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis. Acta Pharm Sin B 2020; 10:1397-1413. [PMID: 32963939 PMCID: PMC7488361 DOI: 10.1016/j.apsb.2020.06.015] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/06/2020] [Accepted: 06/08/2020] [Indexed: 12/24/2022] Open
Abstract
Pyroptosis is a form of programmed cell death, and recently described as a new molecular mechanism of chemotherapy drugs in the treatment of tumors. Miltirone, a derivative of phenanthrene-quinone isolated from the root of Salvia miltiorrhiza Bunge, has been shown to possess anti-cancer activities. Here, we found that miltirone inhibited the cell viability of either HepG2 or Hepa1-6 cells, and induced the proteolytic cleavage of gasdermin E (GSDME) in each hepatocellular carcinoma (HCC) cell line, with concomitant cleavage of caspase 3. Knocking out GSDME switched miltirone-induced cell death from pyroptosis to apoptosis. Additionally, the induction effects of miltirone on GSDME-dependent pyroptosis were attenuated by siRNA-mediated caspase three silencing and the specific caspase three inhibitor Z-DEVD-FMK, respectively. Miltirone effectively elicited intracellular accumulation of reactive oxygen species (ROS), and suppressed phosphorylation of mitogen-activated and extracellular signal-regulated kinase (MEK) and extracellular regulated protein kinases 1/2 (ERK1/2) for pyroptosis induction. Moreover, miltirone significantly inhibited tumor growth and induced pyroptosis in the Hepa1-6 mouse HCC syngeneic model. These results provide a new insight that miltirone is a potential therapeutic agent for the treatment of HCC via GSDME-dependent pyroptosis.
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Key Words
- 7-AAD, 7-aminoactinomycin D
- AKT, AKT serine/threonine kinase, also known as protein kinase B
- ANOVA, analysis of variance
- BAX, BCL2-associated X
- CCK-8, cell counting kit-8
- CRISPR, clustered regularly interspaced short palindromic repeats
- Cas9, caspase 9
- Cell death
- DCFH-DA, dye 2,7-dichlorofluoresce diacetate
- DMEM, Dulbecco's modified Eagle's medium
- DMSO, dimethyl sulfoxide
- ECL, enhanced chemiluminescence
- ERK1/2, extracellular regulated protein kinases 1/2
- FBS, fetal bovine serum
- FITC, fluorescein isothiocyanate
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- GSDMD, gasdermin D
- GSDME
- GSDME, gasdermin E
- H&E, hematoxylin and eosin
- HCC, hepatocellular carcinoma
- HRP, horseradish peroxidase
- HepG2
- Hepa1-6
- Hepatocellular carcinoma
- IC50, the half maximal inhibitory concentration
- IgG (H + L), immunoglobulin G (heavy chain + light chain)
- KO, knockout
- LDH, lactic dehydrogenase
- MEK, mitogen-activated and extracellular signal-regulated kinase
- MEM, minimum essential medium
- MMP, mitochondrial membrane potential
- MS, mass spectrum
- Miltirone
- N-GSDME, N-terminal GSDME
- NAC, N-acetyl cysteine
- NC, negative control
- NMR, nuclear magnetic resonance
- NS, no significance
- PARP, poly ADP-ribose polymerase
- PBS, phosphate-based buffer
- PI, propidium iodide
- PI3K, phosphatidylinositol 3-kinase
- Pyroptosis
- RIPA, radioimmunoprecipitation assay
- ROS, reactive oxygen species
- SD, standard deviation
- SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis
- TBST, Tris-buffered saline with Tween solution
- TCGA, the Cancer Genome Atlas
- VEGF, vascular endothelial growth factor
- gRNA, guide RNA
- i.p., intraperitoneal
- i.v., intravenous
- mTOR, mammalian target of rapamycin
- p-AKT, phosphorylated-AKT
- p-ERK1/2, phosphorylated-ERK1/2
- p-MEK, phosphorylated-MEK
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Insight the Biological Activities of Selected Abietane Diterpenes Isolated from Plectranthus spp. Biomolecules 2020; 10:biom10020194. [PMID: 32012853 PMCID: PMC7072155 DOI: 10.3390/biom10020194] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 01/20/2020] [Accepted: 01/22/2020] [Indexed: 12/19/2022] Open
Abstract
Natural compounds isolated from plants are excellent starting points in drug design and have been widely studied as anticancer agents; they hence find use in a considerable proportion of anticancer drugs. The genus Plectranthus (Lamiaceae) comprises a large and widespread group of species with various applications in traditional medicine. Therefore, the aim of the present study was to determine the effectiveness of treatment with four abietane diterpenoids isolated from P. madagascariensis and P. ecklonii, 6,7-dehydroroyleanone, 7β,6β-dihydroxyroyleanone, 7α-acetoxy-6β-hydroxyroyleanone and parvifloron D, in initiating apoptosis in a glioma cell line. The pure compounds were found to exhibit anticancer effects in primary H7PX glioma cells line by inducing apoptosis G2/M cell cycle arrest and double-strand breaks, indicated by increased levels of phosphorylated H2A.X and decreasing mitochondrial membrane potential; they also influenced the expression of pro- and anti-apoptotic genes (Bax, Bcl-2, TP53, or Cas-3). Our findings indicate that these compounds may offer potential as beneficial antitumor drugs but further in vivo studies are needed.
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Eugenol restricts Cancer Stem Cell population by degradation of β-catenin via N-terminal Ser37 phosphorylation-an in vivo and in vitro experimental evaluation. Chem Biol Interact 2020; 316:108938. [PMID: 31926151 DOI: 10.1016/j.cbi.2020.108938] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/11/2019] [Accepted: 01/06/2020] [Indexed: 11/24/2022]
Abstract
Eugenol a phenylpropanoid, predominantly found in clove is a very common spice in daily cuisine. It already reported to have anti-breast cancer activity. In this study, the effect of eugenol on CSC (Cancer Stem Cell) markers and its main regulator β-catenin both in vivo Ehrlich Ascites Carcinoma (EAC) cell line and in vitro MCF-7 cell line was investigated with that of the untreated group. The therapeutic doses were found to significantly induce apoptosis leaving normal mice and cells unaffected. The in-depth analysis revealed the downregulation of β-catenin thereby facilitating its degradation by N-terminal phosphorylation of Ser37 residue. Significant downregulation of various CSC markers was also observed in vivo after eugenol treatment those are regulated by the intracellular status of β-catenin. These findings were validated by the effect of eugenol on the formation of the secondary sphere in vitro. Notable downregulation of the enriched stemness of secondary mammosphere was detected by the significantly decreased percentage of CD44+/CD24-/low population after eugenol treatment along with their distorted morphology and smaller the number of spheres. The underlying mechanism revealed significant downregulation of β-catenin and the set of CSC markers along with their reduced mRNA expression in secondary sphere culture. Therefore, it can be concluded from the study that eugenol exerts its chemotherapeutic potential by impeding β-catenin nuclear translocation thereby promoting its cytoplasmic degradation as a result stemness is being suppressed potentially even if in the enriched state. Therefore the study contributes to reduce the cancer-induced complications associated with the CSC population. This will ultimately confer the longer and improved patient's life.
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Hu M, Yu Z, Mei P, Li J, Luo D, Zhang H, Zhou M, Liang F, Chen R. Lycorine Induces autophagy-associated apoptosis by targeting MEK2 and enhances vemurafenib activity in colorectal cancer. Aging (Albany NY) 2020; 12:138-155. [PMID: 31901897 PMCID: PMC6977686 DOI: 10.18632/aging.102606] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 12/05/2019] [Indexed: 04/13/2023]
Abstract
Lycorine is a powerful anti-cancer agent against various cancer cell lines with minor side effects. However, the detailed mechanisms of its effects in colorectal cancer (CRC) remain unclear. In this study, we investigated the function and mechanism of lycorine against CRC both in vitro and in vivo. Molecular docking modeling was used to identify potential inhibitory targets of lycorine in CRC. Cell viability was measured using the Cell Counting Kit-8 assay, and apoptosis was measured using flow cytometry. Autophagosomes were examined using transmission electron microscopy and confocal microscopy. HCT116-derived xenografts were constructed to analyze the effect of lycorine in CRC in vivo. Using the CDOCKER algorithm, we determined that lycorine has four interactions with the conserved domain of mitogen-activated protein kinase kinase 2 (MEK2). This prediction was further confirmed by the degradation of phosphorylated MEK2 and its downstream targets after lycorine treatment, and MEK2 overexpression abolished lycorine-induced autophagy-associated apoptosis. Additionally, we revealed that the combination of vemurafenib and lycorine had better effects in CRC models in vitro and in vivo than monotherapy. Our findings identified lycorine as an effective MEK2 inhibitor and suggested that the combination of lycorine and vemurafenib could be used to treat CRC.
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Affiliation(s)
- Man Hu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhaomin Yu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peiyuan Mei
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinxiao Li
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Luo
- Department of Respiratory Medicine, Wuhan First Hospital, Wuhan, China
| | - Haiming Zhang
- Department of Oncology, Integrated Traditional Chinese and Western Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Minfeng Zhou
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Fengxia Liang
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Rui Chen
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Jinushi M, Baghdadi M. Role of Innate Immunity in Cancers and Antitumor Response. CANCER IMMUNOLOGY 2020:11-28. [DOI: 10.1007/978-3-030-30845-2_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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21
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Yang Y, Wu N, Wu Y, Chen H, Qiu J, Qian X, Zeng J, Chiu K, Gao Q, Zhuang J. Artesunate induces mitochondria-mediated apoptosis of human retinoblastoma cells by upregulating Kruppel-like factor 6. Cell Death Dis 2019; 10:862. [PMID: 31723124 PMCID: PMC6853908 DOI: 10.1038/s41419-019-2084-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 09/29/2019] [Accepted: 10/17/2019] [Indexed: 01/28/2023]
Abstract
Retinoblastoma (RB) is the most common primary intraocular malignancy in children. Intravitreal chemotherapy achieves favorable clinical outcomes in controlling RB vitreous seeds, which are a common reason for treatment failure. Thus, a novel, effective and safe intravitreal chemotherapeutic drug is urgently required. The malaria drug artesunate (ART) recently demonstrated remarkable anticancer effects with mild side effects. The purpose of this study is to investigate the anti-RB efficacy, the underlying mechanism and the intraocular safety of ART. Herein, we verified that ART inhibits RB cell viability and induces cell apoptosis in a dose- and time-dependent manner. Microarray analysis revealed that Kruppel-like factor 6 (KLF6) was upregulated after ART treatment, and this was further confirmed by real-time PCR and western blot assays. Silencing of KLF6 expression significantly reversed ART-induced RB cell growth inhibition and apoptosis. Furthermore, ART activated mitochondria-mediated apoptosis of RB cells, while silencing KLF6 expression significantly inhibited this effect. In murine xenotransplantation models of RB, we further confirmed that ART inhibits RB tumor growth, induces tumor cell apoptosis and upregulates KLF6 expression. In addition, KLF6 silencing attenuates ART-mediated inhibition of tumor growth in vivo. Furthermore, we proved that intravitreal injection of ART in Sprague-Dawley (SD) rats is safe, with no obvious retinal function damage or structural disorders observed by electrophysiology (ERG), fundal photographs, fundus fluorescein angiography (FFA) or optical coherence tomography (OCT) examinations. Collectively, our study revealed that ART induces mitochondrial apoptosis of RB cells via upregulating KLF6, and our results may extend the application of ART to the clinic as an effective and safe intravitreal chemotherapeutic drug to treat RB, especially RB with vitreous seeds.
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Affiliation(s)
- Ying Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, P. R. China
| | - Nandan Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, P. R. China
| | - Yihui Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, P. R. China
| | - Haoting Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, P. R. China
| | - Jin Qiu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, P. R. China
| | - Xiaobing Qian
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, P. R. China
| | - Jieting Zeng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, P. R. China
| | - Kin Chiu
- Department of Ophthalmology, The University of Hong Kong, Hong Kong SAR, P. R. China
| | - Qianying Gao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, P. R. China. .,Department of Ophthalmology, The 2nd Affiliate Hospital, Wenzhou Medical University, Wenzhou, 325000, P. R. China.
| | - Jing Zhuang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, P. R. China.
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Zhao Q, Chang W, Chen R, Liu Y. Anti-Proliferative Effect of Wogonin on Ovary Cancer Cells Involves Activation of Apoptosis and Cell Cycle Arrest. Med Sci Monit 2019; 25:8465-8471. [PMID: 31707402 PMCID: PMC6865227 DOI: 10.12659/msm.917823] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The present study was designed to investigate the effect of wogonin on Caov-3 and A2780 ovary cancer cell proliferation and the mechanisms involved. MATERIAL AND METHODS Cell viability changes and apoptosis induction by wogonin were assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenytetrazolium bromide) assay and fluorescence microscopy. Morphological examination of cells was performed using transmission electron microscopy. RESULTS Wogonin exhibited inhibitory effect on Caov-3 and A2780 cancer cell proliferation in a concentration-based manner. Caov-3 and A2780 cell proliferation was reduced to 18% and 21%, respectively on treatment with 200 μM concentration of wogonin. Treatment with wogonin significantly enhanced the percentage of A2780 cells showing apoptosis. The nuclear membrane degradation and condensation of chromatin material was evident in A2780 cells on treatment with wogonin. Treatment of A2780 cells with wogonin suppressed the migration potential significantly. The proportion of A2780 cells in G1/G0 phase was markedly raised on exposure to wogonin for 48 hours. CONCLUSIONS In summary, this study demonstrated that wogonin acts as an ovary cancer cell proliferation inhibiting agent through activation of apoptosis. Wogonin, therefore, can be investigated further for the development of ovary cancer treatment.
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Affiliation(s)
- Qingyang Zhao
- Department of Cadres Medical Care, The Second Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Weiwei Chang
- Analysis and Testing Center, Shandong University of Technology, Zibo, Shandong, China (mainland)
| | - Rui Chen
- Shandong Long Tai Biological Technology Co. Ltd., Jinan, Shandong, China (mainland)
| | - Yanhong Liu
- Department of Obstetrics, The Second Hospital of Shandong University, Jinan, Shandong, China (mainland)
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Yin S, Qiu Y, Jin C, Wang R, Wu S, Liu H, Koo S, Han L, Zhang Y, Gao X, Pang X, Wang T, Yu H. 7‐Deoxynarciclasine shows promising antitumor efficacy by targeting Akt against hepatocellular carcinoma. Int J Cancer 2019; 145:3334-3346. [DOI: 10.1002/ijc.32395] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 05/02/2019] [Indexed: 01/17/2023]
Affiliation(s)
- Shuangshuang Yin
- Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese Medicine Tianjin China
| | - Yuling Qiu
- School of PharmacyTianjin Medical University Tianjin China
| | - Chengyun Jin
- School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and EvaluationZhengzhou University Zhengzhou Henan China
| | - Rui Wang
- Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese Medicine Tianjin China
| | - Song Wu
- Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese Medicine Tianjin China
| | - Hongwei Liu
- Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese Medicine Tianjin China
| | - Sangho Koo
- Department of ChemistryMyongji University Seoul South Korea
| | - Lifeng Han
- Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese Medicine Tianjin China
| | - Yi Zhang
- Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese Medicine Tianjin China
| | - Xiumei Gao
- Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese Medicine Tianjin China
| | - Xu Pang
- Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese Medicine Tianjin China
| | - Tao Wang
- Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese Medicine Tianjin China
| | - Haiyang Yu
- Tianjin State Key Laboratory of Modern Chinese MedicineTianjin University of Traditional Chinese Medicine Tianjin China
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Bahar E, Kim JY, Yoon H. Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling. Cancers (Basel) 2019; 11:cancers11030338. [PMID: 30857233 PMCID: PMC6468910 DOI: 10.3390/cancers11030338] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 03/01/2019] [Accepted: 03/01/2019] [Indexed: 02/06/2023] Open
Abstract
Cancers cells have the ability to develop chemotherapy resistance, which is a persistent problem during cancer treatment. Chemotherapy resistance develops through different molecular mechanisms, which lead to modification of the cancer cells signals needed for cellular proliferation or for stimulating an immune response. The endoplasmic reticulum (ER) is an important organelle involved in protein quality control, by promoting the correct folding of protein and ER-mediated degradation of unfolded or misfolded protein, namely, ER-associated degradation. Disturbances of the normal ER functions causes an accumulation of unfolded or misfolded proteins in the ER lumen, resulting in a condition called “ER stress (ERS).” ERS triggers the unfolded protein response (UPR)—also called the ERS response (ERSR)—to restore homeostasis or activate cell death. Although the ERSR is one emerging potential target for chemotherapeutics to treat cancer, it is also critical for chemotherapeutics resistance, as well. However, the detailed molecular mechanism of the relationship between the ERSR and tumor survival or drug resistance remains to be fully understood. In this review, we aim to describe the most vital molecular mechanism of the relationship between the ERSR and chemotherapy resistance. Moreover, the review also discusses the molecular mechanism of ER stress-mediated apoptosis on cancer treatments.
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Affiliation(s)
- Entaz Bahar
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Gyeongnam, Korea.
| | - Ji-Ye Kim
- Department of Pathology, College of Medicine, Yonsei University, Seoul 03722, Korea.
- Department of Pathology, Ilsan Paik Hospital, Inje University, Goyang 10381, Gyeonggi-do, Korea.
- Department of Pathology, National Cancer Center, Goyang 10408, Gyeonggi-do, Korea.
| | - Hyonok Yoon
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 52828, Gyeongnam, Korea.
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25
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Vitale DL, Spinelli FM, Del Dago D, Icardi A, Demarchi G, Caon I, García M, Bolontrade MF, Passi A, Cristina C, Alaniz L. Co-treatment of tumor cells with hyaluronan plus doxorubicin affects endothelial cell behavior independently of VEGF expression. Oncotarget 2018; 9:36585-36602. [PMID: 30564299 PMCID: PMC6290962 DOI: 10.18632/oncotarget.26379] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 11/07/2018] [Indexed: 12/24/2022] Open
Abstract
Hyaluronan, the main glycosaminoglycan of extracellular matrices, is concentrated in tissues with high cell proliferation and migration rates. In cancer, hyaluronan expression is altered and it becomes fragmented into low-molecular-weight forms, affecting mechanisms associated with cell proliferation, invasion, angiogenesis and multidrug resistance. Here, we analyzed the effect of low-molecular-weight hyaluronan on the response of T lymphoma, osteosarcoma, and mammary adenocarcinoma cell lines to the antineoplastic drug doxorubicin, and whether co-treatment with hyaluronan and doxorubicin modified the behavior of endothelial cells. Our aim was to associate the hyaluronan-doxorubicin response with angiogenic alterations in these tumors. After hyaluronan and doxorubicin co-treatment, hyaluronan altered drug accumulation and modulated the expression of ATP-binding cassette transporters in T-cell lymphoma cells. In contrast, no changes in drug accumulation were observed in cells from solid tumors, indicating that hyaluronan might not affect drug efflux. However, when we evaluated the effect on angiogenic mechanisms, the supernatant from tumor cells treated with doxorubicin exhibited a pro-angiogenic effect on endothelial cells. Hyaluronan-doxorubicin co-treatment increased migration and vessel formation in endothelial cells. This effect was independent of vascular endothelial growth factor but related to fibroblast growth factor-2 expression. Besides, we observed a pro-angiogenic effect on endothelial cells during hyaluronan and doxorubicin co-treatment in the in vivo murine model of T-cell lymphoma. Our results demonstrate for the first time that hyaluronan is a potential modulator of doxorubicin response by mechanisms that involve not only drug efflux but also angiogenic processes, providing an adverse tumor stroma during chemotherapy.
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Affiliation(s)
- Daiana L Vitale
- Laboratorio de Microambiente Tumoral-Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CIT NOBA, UNNOBA-CONICET), Junín, Buenos Aires, Argentina
| | - Fiorella M Spinelli
- Laboratorio de Microambiente Tumoral-Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CIT NOBA, UNNOBA-CONICET), Junín, Buenos Aires, Argentina
| | - Daiana Del Dago
- Laboratorio de Microambiente Tumoral-Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CIT NOBA, UNNOBA-CONICET), Junín, Buenos Aires, Argentina
| | - Antonella Icardi
- Laboratorio de Microambiente Tumoral-Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CIT NOBA, UNNOBA-CONICET), Junín, Buenos Aires, Argentina
| | - Gianina Demarchi
- Laboratorio de Fisiopatología de la Hipófisis-Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CIT NOBA, UNNOBA-CONICET), Junín, Buenos Aires, Argentina
| | - Ilaria Caon
- Dipartimento di Medicina e Chirurgia, Universitá degli Studio dell'Insubria, Varese, Italia
| | - Mariana García
- Laboratorio de Terapia Génica, IIMT-CONICET, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
| | - Marcela F Bolontrade
- Laboratorio de Células Madre-Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Alberto Passi
- Dipartimento di Medicina e Chirurgia, Universitá degli Studio dell'Insubria, Varese, Italia
| | - Carolina Cristina
- Laboratorio de Fisiopatología de la Hipófisis-Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CIT NOBA, UNNOBA-CONICET), Junín, Buenos Aires, Argentina
| | - Laura Alaniz
- Laboratorio de Microambiente Tumoral-Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CIT NOBA, UNNOBA-CONICET), Junín, Buenos Aires, Argentina
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Shen X, Gao X, Li H, Gu Y, Wang J. TIMP-3 Increases the Chemosensitivity of Laryngeal Carcinoma to Cisplatin via Facilitating Mitochondria-Dependent Apoptosis. Oncol Res 2018. [PMID: 29523219 PMCID: PMC7848409 DOI: 10.3727/096504018x15201099883047] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Laryngeal carcinoma is a type of head and neck carcinoma with a high incidence and mortality. Chemotherapy treatments of human laryngeal carcinoma may fail due to the development of chemoresistance. Tissue inhibitor of metalloproteinase 3 (TIMP-3) has been shown to be implicated in a number of pathological processes typical for cancer. The present study aims to investigate the involvement of TIMP-3 in the chemoresistance of laryngeal carcinoma. We showed that TIMP-3 expression was significantly decreased in chemoresistant laryngeal carcinoma tissues compared with chemosensitivity tissues. Patients with low TIMP-3 expression exhibited poorer overall survival than those with high TIMP-3 expression. Moreover, cisplatin-resistant Hep-2 cells (Hep-2/R) were associated with the inhibition of mitochondrial membrane potential (MtMP) depolarization after cisplatin challenge. In addition, cisplatin resulted in a more pronounced mitochondrial cytochrome c release into the cytoplasm in Hep-2 cells than in their resistant variants. Overexpression of TIMP-3 by an adenovirus encoding TIMP-3 cDNA remarkably enhanced cisplatin-induced apoptosis, cytochrome c release, and caspase activation in Hep-2/R cells, thereby sensitizing cancer cells to cisplatin. On the other hand, downregulation of TIMP-3 markedly inhibited cisplatin-induced apoptosis in Hep-2 cells through attenuating mitochondria-dependent pathway activation. Taken together, these results demonstrate that decreased TIMP-3 expression may contribute to cisplatin resistance via inhibition of mitochondria-dependent apoptosis, indicating that forced TIMP-3 expression may be a useful strategy to improve the efficacy of cisplatin to treat laryngeal carcinoma.
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Affiliation(s)
- Xiaohui Shen
- Department of Otolaryngology Head and Neck, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P.R. China
| | - Xia Gao
- Department of Otolaryngology Head and Neck, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P.R. China
| | - Hui Li
- Department of Otolaryngology Head and Neck, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P.R. China
| | - Yajun Gu
- Department of Otolaryngology Head and Neck, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P.R. China
| | - Junguo Wang
- Department of Otolaryngology Head and Neck, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P.R. China
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Niu P, Shi D, Zhang S, Zhu Y, Zhou J. Cardamonin enhances the anti-proliferative effect of cisplatin on ovarian cancer. Oncol Lett 2018; 15:3991-3997. [PMID: 29456744 DOI: 10.3892/ol.2018.7743] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 09/09/2017] [Indexed: 12/19/2022] Open
Abstract
The mammalian target of rapamycin (mTOR) is well-known as a promising therapeutic target in various cancer cells. mTOR activation decreases the sensitivity of ovarian cancer to cisplatin. Cardamonin inhibits the proliferation of various cancer cells by mTOR suppression. The present study examined whether cardamonin combined with cisplatin is efficacious for the anti-proliferation of ovarian cancer cells. The anti-proliferative effect was determined by MTT and cell cycle assays. Activation of the mTOR signal pathway and the expression of anti-apoptotic proteins were evaluated by western blot analysis. Cardamonin significantly enhanced the effects of cisplatin on cell proliferation and cell cycle progression. The expression of B cell lymphoma-2, X-linked inhibitor of apoptosis protein and Survivin was significantly decreased following combination treatment. Furthermore, the activation of mTOR and its downstream 70 kDa ribosomal protein S6 kinase was inhibited by cardamonin. These results demonstrated that the combinatorial effects of cardamonin and cisplatin on anti-proliferation were enhanced by suppressing the expression of anti-apoptotic proteins and activation of mTOR in ovarian cancer cells.
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Affiliation(s)
- Peiguang Niu
- Department of Pharmacy, Fujian Provincial Maternity and Children Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Daohua Shi
- Department of Pharmacy, Fujian Provincial Maternity and Children Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Shusheng Zhang
- Department of Pharmacy, Fujian Provincial Maternity and Children Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Yanting Zhu
- Department of Pharmacy, Fujian Provincial Maternity and Children Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Jintuo Zhou
- Department of Pharmacy, Fujian Provincial Maternity and Children Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
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28
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Videira RA, Andrade PB, Monteiro LS, Valentão P, Ferreira PMT, Pereira DM. Toxicity and structure-activity relationship (SAR) of α,β-dehydroamino acids against human cancer cell lines. Toxicol In Vitro 2017; 47:26-37. [PMID: 29107685 DOI: 10.1016/j.tiv.2017.10.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 10/06/2017] [Accepted: 10/26/2017] [Indexed: 12/18/2022]
Abstract
A library of N-protected dehydroamino acids, namely dehydroalanine, dehydroaminobutyric acid and dehydrophenylalanine derivatives, was screened in three human cancer cell lines [(lung (A549), gastric (AGS) and neuroblastoma (SH-SY5Y)] in order to characterize their toxicological profile and identify new molecules with potential anticancer activity. Results showed N-protected dehydrophenylalanine and dehydroaminobutyric acid derivatives have no or low toxicity for all tested cell lines. The N-protected dehydroalanines exhibit significant toxic effects and the AGS and SH-SY5Y cells were significantly more vulnerable than A549 cells. Four α,β-dehydroalanine derivatives, with IC50<62.5μM, were selected to investigate the pathways by which these compounds promote cell death. All compounds, at their IC50 concentrations, were able to induce apoptosis in both AGS and SH-SY5Y cell lines. In both cell lines, loss of mitochondrial membrane potential (ΔΨm) was found and caspase activity was increased, namely endoplasmic reticulum-resident caspase-4 in AGS cells and caspase-3/7 in SH-SY5Y cells. When evaluated in a non-cancer cell line, the molecules displayed no to low toxicity, thus suggesting some degree of selectivity for cancer cells. The results indicate that α,β-dehydroalanine derivatives can be considered a future resource of compounds able to work as anticancer drugs.
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Affiliation(s)
- Romeu A Videira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, No 228, 4050-213 Porto, Portugal.
| | - Paula B Andrade
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, No 228, 4050-213 Porto, Portugal.
| | - Luís S Monteiro
- Centre of Chemistry, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
| | - Patrícia Valentão
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, No 228, 4050-213 Porto, Portugal.
| | - Paula M T Ferreira
- Centre of Chemistry, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
| | - David M Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, No 228, 4050-213 Porto, Portugal.
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Cao Q, Yan X, Chen K, Huang Q, Melancon MP, Lopez G, Cheng Z, Li C. Macrophages as a potential tumor-microenvironment target for noninvasive imaging of early response to anticancer therapy. Biomaterials 2017; 152:63-76. [PMID: 29111494 DOI: 10.1016/j.biomaterials.2017.10.036] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 09/30/2017] [Accepted: 10/19/2017] [Indexed: 10/18/2022]
Abstract
As a result of therapy-induced apoptosis, peripheral blood monocytes are recruited to tumors, where they become tumor-associated macrophages (TAMs). To date, few studies have investigated noninvasive molecular imaging for assessment of macrophage infiltration in response to therapy-induced apoptosis. Here, noninvasive assessment of changes in tumor accumulation of TAMs was proposed as a new way to measure early tumor response to anticancer therapy. Three different nanoparticles, QD710-Dendron quantum dots (QD710-D), Ferumoxytol, and PG-Gd-NIR813, were used for near-infrared fluorescence imaging, T2-weighted magnetic resonance imaging, and dual optical/T1-weighted MR imaging, respectively, in the MDA-MB-435 tumor model. Treatment with Abraxane induced tumor apoptosis and infiltrating macrophages. In spite of markedly different physicochemical properties among the nanoparticles, in vivo imaging revealed increased uptake of all three nanoparticles in Abraxane-treated tumors compared with untreated tumors. Moreover, imaging visualized increased uptake of QD710-D in MDA-MB-435 tumors but not in drug-resistant MDA-MB-435R tumors grown in the mice treated with Abraxane. Our results suggest that infiltration of macrophages due to chemotherapy-induced apoptosis was partially responsible for increased nanoparticle uptake in treated tumors. Noninvasive imaging techniques in conjunction with systemic administration of imageable nanoparticles that are taken up by macrophages are a potentially useful tool for assessing early treatment response.
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Affiliation(s)
- Qizhen Cao
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, CA, United States
| | - Xinrui Yan
- Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, CA, United States
| | - Kai Chen
- Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, CA, United States
| | - Qian Huang
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Marites P Melancon
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Gabriel Lopez
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Zhen Cheng
- Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, CA, United States.
| | - Chun Li
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Experimental Therapeutics Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, United States.
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Lai YH, Chen J, Wang XP, Wu YQ, Peng HT, Lin XH, Wang WJ. Collagen triple helix repeat containing-1 negatively regulated by microRNA-30c promotes cell proliferation and metastasis and indicates poor prognosis in breast cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:92. [PMID: 28697793 PMCID: PMC5506643 DOI: 10.1186/s13046-017-0564-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/03/2017] [Indexed: 12/18/2022]
Abstract
Background Collagen triple helix repeat containing-1 (CTHRC1), which was firstly identified overexpressed in the adventitia and neointima of injured rat arteries, could inhibit collagen expression and increase cell migration. It was then found to be ubiquitously expressed in numerous cell types such as fibroblasts and smooth muscle cells, and aberrantly up-regulated in several malignant tumors. However, the functional role of CTHRC1 and its related mechanism in breast cancer still remains unclear. Methods CTHRC1 expressions in breast cancer tissues and cells were assessed by qRT-PCR, western blot and immunohistochemistry. The relative expression level of miR-134, miR-155, miR-30c and miR-630 in breast cancer cells respectively was detected by qRT-PCR. Wild type (Wt) and Mutant type (Mut) CTHRC1 3’UTR sequences were cloned into a psi-CHECK2 reporter vector, and the relative luciferase activity was detected by dual-luciferase reporter assay in indicated cells. The effect of ectopic expression of miR-30c or gain and loss of CTHRC1 on cell viability, cell proliferation, cell cycle progression and apoptosis, cell invasion and migration was respectively detected by CCK-8 assay, colony formation assay, flow cytometry analysis, transwell invasion/migration assay. Protein levels of β-catenin, active β-catenin, normal and phosphorylated form of GSK-3β were detected by western blot in indicated cells. Immunofluorescence staining of β-catenin was performed to observe nuclear localization. Results We found CTHRC1 was frequently up-regulated in human breast cancer cells and tissues. Then our cohort study and further meta-analysis validated high expression of CTHRC1 was associated with aggressive clinicopathological features and poor clinical outcome of breast cancer patients. In addition, CTHRC1 promoted cell proliferation, invasion and migration and suppressed cell apoptosis in breast cancer, which might be by activating GSK-3β/β-catenin signaling and inhibiting Bax/Caspase-9/Caspase-3 signaling respectively; and these biological functions of CTHRC1 could be directly negatively regulated by miR-30c. Conclusion Taken together, we identified the role of miR-30c/CTHRC1 axis in breast cancer progression and demonstrated CTHRC1 may serve as a prognostic biomarker and therapeutic target for breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0564-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yuan-Hui Lai
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510700, China
| | - Jian Chen
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510700, China
| | - Xiao-Ping Wang
- Department of Organ Transplantation, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510700, China
| | - Yan-Qing Wu
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510700, China
| | - Hai-Tao Peng
- Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510180, China
| | - Xiao-Hong Lin
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510700, China
| | - Wen-Jian Wang
- Laboratory of Department of Surgery, the First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong, 510080, China.
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2,5-Dihydroxyacetophenone Induces Apoptosis of Multiple Myeloma Cells by Regulating the MAPK Activation Pathway. Molecules 2017; 22:molecules22071157. [PMID: 28696369 PMCID: PMC6152349 DOI: 10.3390/molecules22071157] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 07/03/2017] [Accepted: 07/07/2017] [Indexed: 12/28/2022] Open
Abstract
2,5-Dihydroxyacetophenone (DHAP) is an active compound obtained from Radix rehmanniae preparata, which is widely used as a herbal medicine in many Asian countries. DHAP has been found to possess anti-inflammatory, anti-anxiety, and neuroprotective qualities. For the present study, we evaluated the anti-cancer effects of DHAP on multiple myeloma cells. It was discovered that DHAP downregulated the expression of oncogenic gene products like Bcl-xl, Bcl-2, Mcl-1, Survivin, Cyclin D1, IAP-1, Cyclin E, COX-2, and MMP-9, and upregulated the expression of Bax and p21 proteins, consistent with the induction of G2/M phase cell cycle arrest and apoptosis in U266 cells. DHAP inhibited cell proliferation and induced apoptosis, as characterized by the cleavage of PARP and the activation of caspase-3, caspase-8, and caspase-9. Mitogen-activated protein kinase (MAPK) pathways have been linked to the modulation of the angiogenesis, proliferation, metastasis, and invasion of tumors. We therefore attempted to determine the effect of DHAP on MAPK signaling pathways, and discovered that DHAP treatment induced a sustained activation of JNK, ERK1/2, and p38 MAPKs. DHAP also potentiated the pro-apoptotic and anti-proliferative effects of bortezomib in U266 cells. Our results suggest that DHAP can be an effective therapeutic agent to target multiple myeloma.
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Dichloromethane fraction of Asiasarum heterotropoides induces S phase arrest and apoptosis in KB oral epithelial carcinoma cells. Biomed Pharmacother 2017; 89:559-564. [DOI: 10.1016/j.biopha.2017.02.072] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 02/12/2017] [Accepted: 02/20/2017] [Indexed: 11/18/2022] Open
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A stimuli responsive liposome loaded hydrogel provides flexible on-demand release of therapeutic agents. Acta Biomater 2017; 48:110-119. [PMID: 27773752 DOI: 10.1016/j.actbio.2016.10.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 09/29/2016] [Accepted: 10/02/2016] [Indexed: 12/22/2022]
Abstract
Lysolipid-based thermosensitive liposomes (LTSL) embedded in a chitosan-based thermoresponsive hydrogel matrix (denoted Lipogel) represents a novel approach for the spatiotemporal release of therapeutic agents. The entrapment of drug-loaded liposomes in an injectable hydrogel permits local liposome retention, thus providing a prolonged release in target tissues. Moreover, release can be controlled through the use of a minimally invasive external hyperthermic stimulus. Temporal control of release is particularly important for complex multi-step physiological processes, such as angiogenesis, in which different signals are required at different times in order to produce a robust vasculature. In the present work, we demonstrate the ability of Lipogel to provide a flexible, easily modifiable release platform. It is possible to tune the release kinetics of different drugs providing a passive release of one therapeutic agent loaded within the gel and activating the release of a second LTSL encapsulated agent via a hyperthermic stimulus. In addition, it was possible to modify the drug dosage within Lipogel by varying the duration of hyperthermia. This can allow for adaption of drug dosing in real time. As an in vitro proof of concept with this system, we investigated Lipogels ability to recruit stem cells and then elevate their production of vascular endothelial growth factor (VEGF) by controlling the release of a pro-angiogenic drug, desferroxamine (DFO) with an external hyperthermic stimulus. Initial cell recruitment was accomplished by the passive release of hepatocyte growth factor (HGF) from the hydrogel, inducing a migratory response in cells, followed by the delayed release of DFO from thermosensitive liposomes, resulting in a significant increase in VEGF expression. This delayed release could be controlled up to 14days. Moreover, by changing the duration of the hyperthermic pulse, a fine control over the amount of DFO released was achieved. The ability to trigger the release of therapeutic agents at a specific timepoint and control dosing level through changes in duration of hyperthermia enables sequential multi-dose profiles. STATEMENT OF SIGNIFICANCE This paper details the development of a heat responsive liposome loaded hydrogel for the controlled release of pro-angiogenic therapeutics. Lysolipid-based thermosensitive liposomes (LTSLs) embedded in a chitosan-based thermoresponsive hydrogel matrix represents a novel approach for the spatiotemporal release of therapeutic agents. This hydrogel platform demonstrates remarkable flexibility in terms of drug scheduling and sequencing, enabling the release of multiple agents and the ability to control drug dosing in a minimally invasive fashion. The possibility to tune the release kinetics of different drugs independently represents an innovative platform to utilise for a variety of treatments. This approach allows a significant degree of flexibility in achieving a desired release profile via a minimally invasive stimulus, enabling treatments to be tuned in response to changing symptoms and complications.
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Vanitha S, Chaubey N, Ghosh SS, Sanpui P. Recombinant human granulocyte macrophage colony stimulating factor (hGM-CSF): Possibility of nanoparticle-mediated delivery in cancer immunotherapy. Bioengineered 2016; 8:120-123. [PMID: 27459024 DOI: 10.1080/21655979.2016.1212136] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Most of the cancer treatment strategies from chemotherapy to radiotherapy render cancer cells apoptotic and these apoptotic cancer cells accumulate at the tumor sites. The accumulation of apoptotic cancer cells often result in inflammation and autoimmune responses causing serious health implications. Macrophages, which are effective immune combatants, can help in the clearance of these deleterious occupants. Granulocyte macrophage colony stimulating factor (GM-CSF) is a key cytokine, modulator of immune system and responsible for growth and differentiation of granulocytes and macrophages. In this regard, supply of recombinant GM-CSF can enhance the capability of macrophages for clearance of apoptotic cancer cells. However, delivery of the cytokine in vivo can suffer from certain disadvantages like faster depletion, less stability and low targeting efficiency. We believe that the stability and sustained release of GM-CSF can be improved through its encapsulation inside appropriately designed nanoparticles.
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Affiliation(s)
- Selvarajan Vanitha
- a Department of Biosciences and Bioengineering , Indian Institute of Technology Guwahati , Assam , India
| | - Nidhi Chaubey
- a Department of Biosciences and Bioengineering , Indian Institute of Technology Guwahati , Assam , India
| | - Siddhartha S Ghosh
- a Department of Biosciences and Bioengineering , Indian Institute of Technology Guwahati , Assam , India.,b Centre for Nanotechnology, Indian Institute of Technology Guwahati , Assam , India
| | - Pallab Sanpui
- b Centre for Nanotechnology, Indian Institute of Technology Guwahati , Assam , India
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Firempong CK, Zhang HY, Wang Y, Chen J, Cao X, Deng W, Zhou J, Wang Q, Tong SS, Yu J, Xu X. Segetoside I, a plant-derived bisdesmosidic saponin, induces apoptosis in human hepatoma cells in vitro and inhibits tumor growth in vivo. Pharmacol Res 2016; 110:101-110. [PMID: 27180010 DOI: 10.1016/j.phrs.2016.04.032] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 04/27/2016] [Accepted: 04/28/2016] [Indexed: 10/21/2022]
Abstract
Segetoside I is a plant-derived bisdesmosidic saponin from Vaccaria segetalis (Neck) with reported anticancer activities. This development has raised an interest in the therapeutic potential of segetoside I. Here, we report the in vitro and in vivo antitumor activities of segetoside I against some selected cancer cell lines (HepG2, human hepatoma; H22, mouse hepatoma; MCF-7, breast cancer; U251, gliocoma; BGC, HGC & SGC, gastric cancinoma; Lovo-1,colon cancer). MTT bioassay analysis showed that HepG2 cells were the most sensitive to segetoside I compared with other cancer cell lines, with lower toxicity in healthy mouse embryonic fibroblast cells. Segetoside I pretreatment of HepG2 resulted in apoptotic induction, dose-dependent DNA fragmentation, inhibition of cell migration, up-regulation of Bax and down-regulation of Bcl-2, which indicated that an apoptotic signaling event could have been initiated. The segetoside I also suppressed hepato-tumour growth in mice with virtually no cytotoxicity and prolonged animal survival, making it a strong oncology drug agent. These findings showed that segetoside I exhibited its antitumor activity via apoptotic induction and significantly support the possible application of the antitumor agent as a potential chemotherapeutic candidate worthy of further investigations.
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Affiliation(s)
- Caleb Kesse Firempong
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China; Department of Biochemistry and Biotechnology, College of Science, KwameNkrumah University of Science and Technology, Kumasi-Ghana
| | - Hui Yun Zhang
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China
| | - Yan Wang
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China
| | - Jingjing Chen
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China
| | - Xia Cao
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China
| | - Wenwen Deng
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China
| | - Jie Zhou
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China
| | - Qiang Wang
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China
| | - Shan-Shan Tong
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China
| | - Jiangnan Yu
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China; School of Pharmacy, China Pharmaceutical University, Nanjing, PR China
| | - Ximing Xu
- Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, PR China.
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Salem ML, Shoukry NM, Teleb WK, Abdel-Daim MM, Abdel-Rahman MA. In vitro and in vivo antitumor effects of the Egyptian scorpion Androctonus amoreuxi venom in an Ehrlich ascites tumor model. SPRINGERPLUS 2016; 5:570. [PMID: 27247867 PMCID: PMC4864766 DOI: 10.1186/s40064-016-2269-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 05/03/2016] [Indexed: 02/07/2023]
Abstract
Scorpion venom is a highly complex mixture of about 100-700 different components, where peptides are the major constituents with various biological and pharmacological properties including anticancer activities. In this study, anticancer efficacy of the venom of the Egyptian scorpion Androctonus amoreuxi has been evaluated. In vitro, the human breast cancer MCF-7 cell line was treated with the venom and the IC50 was estimated. In vivo studies, Ehrlich ascites carcinoma (EAC) cells were inoculated into CD-1 mice intraperitoneally to form liquid tumor or subcutaneously to form solid tumor and then treated with intraperitoneal injection with venom (0.22 mg/kg) every other day. The total tumor cells in the ascitic fluid and the size of the solid tumor were assessed after 14 and 30 days, respectively. In addition, the mean survival time (MST), body weight, tumor volume, PCV, viability of tumor cells, CBC, AST, ALP, creatinine, oxidative stress biomarkers (GSH, MDA, PCC), tumor marker Ki67, growth factor VEGF and caspase-3 were measured in normal control, EAC control and venom-treated groups (n = 6). Treatment with venom induced anti-tumor effects against liquid and in solid tumors as indicated by a significant (P < 0.05) reduction in tumor volume/size, count of viable EAC cells, expression of Ki67 and VEGF as well as by remarkable increases in MST and caspase-3 expression as compared to non-treated group. Interestingly, the venom restored the altered hematological and biochemical parameters of tumor-bearing animals and significantly increased their life span. These data indicate to (1) the cytotoxic potential effects of A. amoreuxi on tumor cells via anti-proliferative, apoptotic and anti-angiogenic activities; (2) opening a new avenue for further studies on the anti-cancer effects of this agent.
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Affiliation(s)
- Mohamed L. Salem
- />Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
| | - Nahla M. Shoukry
- />Zoology Department, Faculty of Science, Suez University, Suez, Egypt
| | - Wafaa K. Teleb
- />Zoology Department, Faculty of Science, Suez University, Suez, Egypt
| | - Mohamed M. Abdel-Daim
- />Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522 Egypt
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Affiliation(s)
- Joanna L Fox
- MRC Toxicology Unit, Hodgkin Building, Leicester, LE1 9HN, UK
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Sharifi S, Barar J, Hejazi MS, Samadi N. Doxorubicin Changes Bax /Bcl-xL Ratio, Caspase-8 and 9 in Breast Cancer Cells. Adv Pharm Bull 2015; 5:351-9. [PMID: 26504757 DOI: 10.15171/apb.2015.049] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 11/20/2014] [Accepted: 03/01/2015] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Doxorubicin is administrated as a single agent in first-line therapy of breast cancer to induce apoptosis in tumor cells. Bax, Bcl-xL, Caspase-8 and 9 proteins are involved in induction of apoptosis. The present study describes Bax, Bcl-xL gene expression and Caspase-8 and 9 protein levels in MCF-7 cells incubated with doxorubicin at different doses an incubation times. METHODS The cytotoxic effects of doxorubicin were studied using MTT assay. MCF-7 cells were treated with three concentrations of doxorubicin (0.1, 0.5, 1 μM) and incubated for 24, 48 and 72 hours then expression levels of Bax and Bcl-xL genes were elucidated by Real-time RT-PCR technique and protein levels of caspase-8 and caspase-9 proteins were measured using ELISA method. Morphological modifications of the cells were also monitored via light microscopic images. RESULTS Doxorubicin decreased the anti-apoptotic Bcl-xL and increased pro-apoptotic Bax mRNA levels. Doxorubicin induced a significant increase in Bax /Bcl-xL ratio in all doses and incubation times (p<0.05). Highest (more than 10 fold) increase in Bax /Bcl-xL ratio was revealed after 48 h incubation of the cells with in all doses of doxorubicin. Doxorubicin also increased caspase-9 level in a time and dose-dependent manner, while caspase-8 level didn't follow time and dose dependency pattern. CONCLUSION Our results confirm that doxorubicin induces mitochondrial-dependent apoptosis by down-regulation of Bcl-xL and up- regulation of Bax and caspase-9 expressions.
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Affiliation(s)
- Simin Sharifi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. ; Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jaleh Barar
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. ; Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Saeid Hejazi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. ; Faculty of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran. ; Faculty of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. ; Department of Biochemistry and Medical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Fox JL, Storey A. BMX Negatively Regulates BAK Function, Thereby Increasing Apoptotic Resistance to Chemotherapeutic Drugs. Cancer Res 2015; 75:1345-55. [PMID: 25649765 DOI: 10.1158/0008-5472.can-14-1340] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 01/20/2015] [Indexed: 12/31/2022]
Abstract
The ability of chemotherapeutic agents to induce apoptosis, predominantly via the mitochondrial (intrinsic) apoptotic pathway, is thought to be a major determinant of the sensitivity of a given cancer to treatment. Intrinsic apoptosis, regulated by the BCL2 family, integrates diverse apoptotic signals to determine cell death commitment and then activates the nodal effector protein BAK to initiate the apoptotic cascade. In this study, we identified the tyrosine kinase BMX as a direct negative regulator of BAK function. BMX associates with BAK in viable cells and is the first kinase to phosphorylate the key tyrosine residue needed to maintain BAK in an inactive conformation. Importantly, elevated BMX expression prevents BAK activation in tumor cells treated with chemotherapeutic agents and is associated with increased resistance to apoptosis and decreased patient survival. Accordingly, BMX expression was elevated in prostate, breast, and colon cancers compared with normal tissue, including in aggressive triple-negative breast cancers where BMX overexpression may be a novel biomarker. Furthermore, BMX silencing potentiated BAK activation, rendering tumor cells hypersensitive to otherwise sublethal doses of clinically relevant chemotherapeutic agents. Our finding that BMX directly inhibits a core component of the intrinsic apoptosis machinery opens opportunities to improve the efficacy of existing chemotherapy by potentiating BAK-driven cell death in cancer cells.
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Affiliation(s)
- Joanna L Fox
- Department of Oncology, WIMM, University of Oxford, Oxford, United Kingdom.
| | - Alan Storey
- Department of Oncology, WIMM, University of Oxford, Oxford, United Kingdom.
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Jinushi M, Baghdadi M. Role of Innate Immunity in Cancers and Antitumor Response. CANCER IMMUNOLOGY 2015:29-46. [DOI: 10.1007/978-3-662-44006-3_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Moirangthem DS, Laishram S, Borah JC, Kalita MC, Talukdar NC. Cephalotaxus griffithii Hook.f. needle extract induces cell cycle arrest, apoptosis and suppression of hTERT and hTR expression on human breast cancer cells. Altern Ther Health Med 2014; 14:305. [PMID: 25135691 PMCID: PMC4155093 DOI: 10.1186/1472-6882-14-305] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 08/13/2014] [Indexed: 12/18/2022]
Abstract
Background Cephalotaxus spp. are known to possess anticancer potential. In this present work, for the first time the effects of C. griffithii needle (CGN) extracts on human cancer cells were examined. Methods The CGN was successively extracted with petroleum ether (PE), acetone and methanol. The extracts were tested for its effect on proliferation of cancer cells (MTT assay on HeLa, ZR751 and HepG2). Extract that showed the maximum growth inhibitory effect was subjected for mechanism of action study. These included apoptosis (morphological and DNA fragmentation assay), cell cycle (flow cytometry), caspase expression (Western blot) and activity (assay kit), p53 (western blot and TP53 siRNA interference) and telomerase expression (reverse transcriptase PCR) analysis. Results Among the extracts, PE extract induced maximum cytotoxicity, with highest death occurred in ZR751 cells. Since, PE extract induced cell death was highest among the CGN extracts, with maximum cancer cell death occurred in ZR751 cells; we carried out mechanism study of PE extract induced ZR751 cell death. It was observed that PE extract induced ZR751 cell death was associated with cell cycle arrest and apoptosis by activating both intrinsic and extrinsic apoptotic pathways. Knock down study revealed that p53 is essential for loss of ZR751 cell viability induced by PE extract. Further, PE extract down-regulated hTERT, hTR, and c-Myc expression. Thin layer chromatography analysis indicated the presence of unique phytochemicals in PE extract. Conclusion Based on the observations, we concluded that PE extract of C. griffithii needle contains important phyto-components with multiple cellular targets for control of breast cancer and is worthy of future studies. Electronic supplementary material The online version of this article (doi:10.1186/1472-6882-14-305) contains supplementary material, which is available to authorized users.
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Youns M, Fathy GM. Upregulation of extrinsic apoptotic pathway in curcumin-mediated antiproliferative effect on human pancreatic carcinogenesis. J Cell Biochem 2014; 114:2654-65. [PMID: 23794119 DOI: 10.1002/jcb.24612] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 06/11/2013] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer is one of the most lethal human cancers, with almost identical incidence and mortality rates. Curcumin, derived from the rhizome of Curcuma longa, has a long history of use as coloring agent and for a wide variety of disorders. Here, the antiproliferative activity of curcumin and its modulatory effect on gene expression of pancreatic cancer cell lines were investigated. The effect of curcumin on cellular proliferation and viability was monitored by sulphurhodamine B assay. Apoptotic effect was evaluated by flow cytometry and further confirmed by measuring amount of cytoplasmic histone-associated DNA fragments. Analysis of gene expression was performed with and without curcumin treatment using microarray expression profiling techniques. Array results were confirmed by real-time PCR. ingenuity pathway analysis (IPA) has been used to classify the list of differentially expressed genes and to indentify common biomarkergenes modulating the chemopreventive effect of curcumin. Results showed that curcumin induces growth arrest and apoptosis in pancreatic cancer cell lines. Its effect was more obvious on the highly COX-2 expressing cell line. Additionally, the expression of 366 and 356 cancer-related genes, involved in regulation of apoptosis, cell cycle, metastasis, was significantly altered after curcumin treatment in BxPC-3 and MiaPaCa-2 cells, respectively. Our results suggested that up-regulation of the extrinsic apoptotic pathway was among signaling pathways modulating the growth inhibitory effects of curcumin on pancreatic cancer cells. Curcumin effect was mediated through activation of TNFR, CASP 8, CASP3, BID, BAX, and down-regulation of NFκB, NDRG 1, and BCL2L10 genes.
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Affiliation(s)
- Mahmoud Youns
- Department of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany; Faculty of Pharmacy, Department of Biochemistry and Molecular Biology, Helwan University, Cairo, Egypt
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Parfieniuk-Kowerda A, Lapinski TW, Rogalska-Plonska M, Swiderska M, Panasiuk A, Jaroszewicz J, Flisiak R. Serum cytochrome c and m30-neoepitope of cytokeratin-18 in chronic hepatitis C. Liver Int 2014; 34:544-50. [PMID: 23981197 DOI: 10.1111/liv.12297] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 07/28/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Cytochrome c (CYC) and M30-neoepitope of cytokeratin-18 (M30-CK18) are involved at different levels in apoptotic pathways. We aimed to evaluate an association between serum CYC, M30-CK18 and disease activity as well response to therapy in chronic hepatitis C (CHC). METHODS Seventy CHC patients were enrolled in this study. Forty five of them completed pegylated interferon plus ribavirin therapy. Histopathological evaluation of hepatic inflammatory activity and fibrosis, as well as blood liver function tests, was performed. Serum concentrations of M30-CK18 and CYC were measured by ELISA. RESULTS Median serum concentration of M30-CK18 was higher in CHC patients [283 U/L] vs. control [113 U/L] (P = 0.0003) and was associated with inflammatory activity and liver fibrosis (P < 0.001). Serum M30-CK18 positively correlated with serum activity of ALT and GGT. CYC was not detected in sera of control group, whereas in CHC, 41.43% patients had detectable CYC in serum samples [0.60 ng/ml]. Detectable baseline serum CYC had been negatively associated with sustained virological response (SVR). In patients with detectable CYC, SVR rate was 20% vs. 60% in patients with undetectable CYC (P = 0.007). CONCLUSIONS Elevated serum M30-CK18, as an indicator of enhanced apoptosis of hepatocytes, parallels active hepatic inflammation and fibrosis but also biochemical activity in CHC; thus, it may serve as a comprehensive non-invasive marker of disease activity. On the other hand, detection of serum CYC at baseline may be negatively associated with treatment response to pegylated interferon plus ribavirin in CHC.
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Affiliation(s)
- Anna Parfieniuk-Kowerda
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
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Delayed triggering of oestrogen induced apoptosis that contrasts with rapid paclitaxel-induced breast cancer cell death. Br J Cancer 2014; 110:1488-96. [PMID: 24548860 PMCID: PMC3960622 DOI: 10.1038/bjc.2014.50] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 12/18/2013] [Accepted: 01/08/2014] [Indexed: 01/24/2023] Open
Abstract
Background: Oestrogen (E2) induces apoptosis in long-term E2-deprived MCF7 cells (MCF7:5C). Taxanes have been used extensively in the treatment of early and advanced breast cancer. We have interrogated the sequence of events that involve the apoptotic signalling pathway induced by E2 in comparison with paclitaxel. Methods: DNA quantification and cell cycle analysis were used to assess proliferation of cancer cells. Apoptosis was evaluated using annexin V and DNA staining methods. Regulation of apoptotic genes was determined by performing PCR-based arrays and RT–PCR. Results: E2-induced apoptosis is a delayed process, whereas paclitaxel immediately inhibits the growth and induces death of MCF7:5C cells. The cellular commitment for E2-triggered apoptosis occur after 24 h. Activation of the intrinsic pathway was observed by 36 h of E2 treatment with subsequent induction of the extrinsic apoptotic pathway by 48 h. Paclitaxel exclusively activated extramitochodrial apoptotic genes and caused rapid G2/M blockade by 12 h of treatment. By contrast, E2 causes an initial proliferation with elevated S phase of cell cycles followed by apoptosis of the MCF7:5C cells. Most importantly, we are the first to document that E2-induced apoptosis can be reversed after 24 h treatment. Conclusions: These data indicate that E2-induced apoptosis involves a novel, multidynamic process that is distinctly different from that of a classic cytotoxic chemotherapeutic drug used in breast cancer.
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Wang W, Fang C, Wang X, Chen Y, Wang Y, Feng W, Yan C, Zhao M, Peng S. Modifying mesoporous silica nanoparticles to avoid the metabolic deactivation of 6-mercaptopurine and methotrexate in combinatorial chemotherapy. NANOSCALE 2013; 5:6249-6253. [PMID: 23680872 DOI: 10.1039/c3nr00227f] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Mesoporous silica nanoparticles with amino and thiol groups (MSNSN) were prepared and covalently modified with methotrexate and 6-mercaptopurine to form 6-MP-MSNSN-MTX. In the presence of DTT, 6-MP-MSNSN-MTX gradually releases 6-MP. In rat plasma, 6-MP-MSNSN-MTX effectively inhibits the metabolic deactivation of 6-MP and MTX. 6-MP-MSNSN-MTX could be an agent for long-acting chemotherapy.
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Affiliation(s)
- Wenjing Wang
- College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
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Han C, Zhao R, Kroger J, Qu M, Wani AA, Wang QE. Caspase-2 short isoform interacts with membrane-associated cytoskeleton proteins to inhibit apoptosis. PLoS One 2013; 8:e67033. [PMID: 23840868 PMCID: PMC3698186 DOI: 10.1371/journal.pone.0067033] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 05/13/2013] [Indexed: 12/21/2022] Open
Abstract
Caspase-2 (casp-2) is the most conserved caspase across species, and is one of the initiator caspases activated by various stimuli. The casp-2 gene produces several alternative splicing isoforms. It is believed that the long isoform, casp-2L, promotes apoptosis, whereas the short isoform, casp-2S, inhibits apoptosis. The actual effect of casp-2S on apoptosis is still controversial, however, and the underlying mechanism for casp-2S-mediated apoptosis inhibition is unclear. Here, we analyzed the effects of casp-2S on DNA damage induced apoptosis through "gain-of-function" and "loss-of-function" strategies in ovarian cancer cell lines. We clearly demonstrated that the over-expression of casp-2S inhibited, and the knockdown of casp-2S promoted, the cisplatin-induced apoptosis of ovarian cancer cells. To explore the mechanism by which casp-2S mediates apoptosis inhibition, we analyzed the proteins which interact with casp-2S in cells by using immunoprecipitation (IP) and mass spectrometry. We have identified two cytoskeleton proteins, Fodrin and α-Actinin 4, which interact with FLAG-tagged casp-2S in HeLa cells and confirmed this interaction through reciprocal IP. We further demonstrated that casp-2S (i) is responsible for inhibiting DNA damage-induced cytoplasmic Fodrin cleavage independent of cellular p53 status, and (ii) prevents cisplatin-induced membrane blebbing. Taken together, our data suggests that casp-2S affects cellular apoptosis through its interaction with membrane-associated cytoskeletal Fodrin protein.
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Affiliation(s)
- Chunhua Han
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Ran Zhao
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - John Kroger
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
| | - Meihua Qu
- Department of Pharmacology, Weifang Medical University, Weifang, China
| | - Altaf A. Wani
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Qi-En Wang
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail:
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Liu Y, Lou G, Wu W, Shi Y, Zheng M, Chen Z. Interferon-α sensitizes HBx-expressing hepatocarcinoma cells to chemotherapeutic drugs through inhibition of HBx-mediated NF-κB activation. Virol J 2013; 10:168. [PMID: 23718853 PMCID: PMC3680016 DOI: 10.1186/1743-422x-10-168] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2012] [Accepted: 04/11/2013] [Indexed: 01/15/2023] Open
Abstract
Background Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is characterized by high chemotherapy resistance; however, the underlying mechanism has not been fully clarified. In addition, HBx protein has been reported to play a key role in virus-mediated hepatocarcinogenesis. Therefore, the present study aims to investigate the role of HBx in the drug-resistance of HBV-related HCC and examine whether such drug-resistance can be reversed by IFN-α treatment. Methods We established HBx-expressing cells by liposome-mediated transfection of HBx into the Huh7 cell line. MTT, Annexin V/PI, and cell cycle assay were used for determining the cellular growth inhibition, apoptosis, and growth arrest, respectively, after treatment with chemical drug. We further used tumor-bearing mice model to compare the tumor growth inhibition efficacy of ADM and 5-FU between the Huh7-HBx group and the control group, as well as the ADM + IFN-α or ADM + IMD treated group and the ADM treated group. SQ-Real time-PCR was performed to analyze the expression of MDR-associated genes and anti-apoptotic genes. Moreover, immunofluorescence and Western blotting were used to determine the subcellular localization of p65 and the phosphorylation of IκBα. Results The IC50 values of Huh7-HBx cells against ADM and Amn were 2.317 and 1.828-folds higher than those of Huh7-3.1 cells, respectively. The apoptosis ratio and growth arrest was significantly lower in Huh7-HBx cells after treatment with ADM. The in vivo experiment also confirmed that the Huh7-HBx group was much more resistant to ADM or 5-FU than the control. Furthermore, the expression of MDR-associated genes, such as MDR1, MRP1, LRP1, and ABCG2, were significantly up-regulated in Huh7-HBx cells, and the NF-κB pathway was activated after HBx gene transfection in Huh7 cells. However, combined with IFN-α in ADM treatment, the HBx induced drug-resistance in Huh7-HBx cells can be partly abolished in in vitro and in vivo models. Moreover, we found that the NF-κB canonical pathway was affected by IFN-α treatment, and the expression of anti-apoptotic genes, such as Gadd45β, Survivin, and c-IAP-1 was down-regulated by IFN-α treatment in a dose-dependent manner. Conclusions HBx protein can induce MDR of HBV-related HCC by activating the NF-κB pathway, which can be partly abolished by IFN-α treatment.
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Affiliation(s)
- Yanning Liu
- State Key Laboratory of Infectious Disease Diagnosis and Treatment, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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Liu Y, Lou G, Wu W, Shi Y, Zheng M, Chen Z. Interferon-α sensitizes HBx-expressing hepatocarcinoma cells to chemotherapeutic drugs through inhibition of HBx-mediated NF-κB activation. Virol J 2013. [PMID: 23718853 DOI: 10.1186/1743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is characterized by high chemotherapy resistance; however, the underlying mechanism has not been fully clarified. In addition, HBx protein has been reported to play a key role in virus-mediated hepatocarcinogenesis. Therefore, the present study aims to investigate the role of HBx in the drug-resistance of HBV-related HCC and examine whether such drug-resistance can be reversed by IFN-α treatment. METHODS We established HBx-expressing cells by liposome-mediated transfection of HBx into the Huh7 cell line. MTT, Annexin V/PI, and cell cycle assay were used for determining the cellular growth inhibition, apoptosis, and growth arrest, respectively, after treatment with chemical drug. We further used tumor-bearing mice model to compare the tumor growth inhibition efficacy of ADM and 5-FU between the Huh7-HBx group and the control group, as well as the ADM + IFN-α or ADM + IMD treated group and the ADM treated group. SQ-Real time-PCR was performed to analyze the expression of MDR-associated genes and anti-apoptotic genes. Moreover, immunofluorescence and Western blotting were used to determine the subcellular localization of p65 and the phosphorylation of IκBα. RESULTS The IC₅₀ values of Huh7-HBx cells against ADM and Amn were 2.317 and 1.828-folds higher than those of Huh7-3.1 cells, respectively. The apoptosis ratio and growth arrest was significantly lower in Huh7-HBx cells after treatment with ADM. The in vivo experiment also confirmed that the Huh7-HBx group was much more resistant to ADM or 5-FU than the control. Furthermore, the expression of MDR-associated genes, such as MDR1, MRP1, LRP1, and ABCG2, were significantly up-regulated in Huh7-HBx cells, and the NF-κB pathway was activated after HBx gene transfection in Huh7 cells. However, combined with IFN-α in ADM treatment, the HBx induced drug-resistance in Huh7-HBx cells can be partly abolished in in vitro and in vivo models. Moreover, we found that the NF-κB canonical pathway was affected by IFN-α treatment, and the expression of anti-apoptotic genes, such as Gadd45β, Survivin, and c-IAP-1 was down-regulated by IFN-α treatment in a dose-dependent manner. CONCLUSIONS HBx protein can induce MDR of HBV-related HCC by activating the NF-κB pathway, which can be partly abolished by IFN-α treatment.
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Affiliation(s)
- Yanning Liu
- State Key Laboratory of Infectious Disease Diagnosis and Treatment, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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Yuan BZ, Chapman J, Ding M, Wang J, Jiang B, Rojanasakul Y, Reynolds SH. TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages. BMC Cancer 2013; 13:140. [PMID: 23517112 PMCID: PMC3665596 DOI: 10.1186/1471-2407-13-140] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 03/12/2013] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments. METHODS Proteasome inhibitors (PIs) and TNFα-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM. RESULTS Treatment with 0.5-1 μM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10-20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells. CONCLUSION The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs.
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Elkady AI. Crude alkaloid extract of Rhazya stricta inhibits cell growth and sensitizes human lung cancer cells to cisplatin through induction of apoptosis. Genet Mol Biol 2013; 36:12-21. [PMID: 23569403 PMCID: PMC3615516 DOI: 10.1590/s1415-47572013005000009] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Accepted: 09/28/2012] [Indexed: 12/13/2022] Open
Abstract
There is an urgent need to improve the clinical management of non-small cell lung cancer (NSCLC), one of the most frequent causes of cancer-related deaths in men and women worldwide. Rhazya stricta, an important medicinal plant used in traditional Oriental medicine, possesses anti-oxidant, anti-carcinogenic and free radical scavenging properties. This study was done to explore the potential anticancer activity of a crude alkaloid extract of R. stricta (CAERS) against the NSCLC line A549. CAERS markedly suppressed the growth of A549 cells and considerably enhanced the anti-proliferative potential of cisplatin. CAERS-mediated inhibition of A549 cell growth correlated with the induction of apoptosis that was accompanied by numerous morphological changes, DNA fragmentation, an increase in the Bax/Bcl-2 ratio, the release of mitochondrial cytochrome c, activation of caspases 3 and 9 and cleavage of poly(ADP-ribose)-polymerase. CAERS reduced the constitutive expression of anti-apoptotic proteins (Bcl-2, Bcl-XL, Mcl-1 and Survivin) and cell cycle regulating proteins (cyclin D1 and c-Myc), but enhanced expression of the proapoptotic proteins Noxa and BAD. These observations indicate that CAERS induced apoptosis and sensitized NSCLC to cisplatin via a mitochondria-mediated apoptotic pathway. These data provide a rationale for using a combination of CAERS and CDDP to treat NSCLC and other CDDP-resistant tumors.
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Affiliation(s)
- Ayman I Elkady
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
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