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Álvarez-Carrasco P, Morales-Villamil F, Maldonado-Bernal C. P-Glycoprotein as a Therapeutic Target in Hematological Malignancies: A Challenge to Overcome. Int J Mol Sci 2025; 26:4701. [PMID: 40429842 PMCID: PMC12112708 DOI: 10.3390/ijms26104701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 05/07/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
P-glycoprotein (P-gp), a transmembrane efflux pump encoded by the ABCB1/MDR1 gene, is a major contributor to multidrug resistance in hematological malignancies. These malignancies, arising from hematopoietic precursors at various differentiation stages, can manifest in the bone marrow, circulate in the bloodstream, or infiltrate tissues. P-gp overexpression in malignant cells reduces the efficacy of chemotherapeutic agents by actively expelling them, decreasing intracellular drug concentrations, and promoting multidrug resistance, a significant obstacle to successful treatment. This review examines recent advances in combating P-gp-mediated resistance, including the development of novel P-gp inhibitors, innovative drug delivery systems (e.g., nanoparticle-based delivery), and strategies to modulate P-gp expression or activity. These modulation strategies encompass targeting relevant signaling pathways (e.g., NF-κB, PI3K/Akt) and exploring drug repurposing. While progress has been made, overcoming P-gp-mediated resistance remains crucial for improving patient outcomes. Future research directions should prioritize the development of potent, selective, and safe P-gp inhibitors with minimal off-target effects, alongside exploring synergistic combination therapies with existing chemotherapeutics or novel agents to effectively circumvent multidrug resistance in hematological malignancies.
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MESH Headings
- Humans
- Hematologic Neoplasms/drug therapy
- Hematologic Neoplasms/metabolism
- Drug Resistance, Neoplasm/drug effects
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Animals
- Drug Resistance, Multiple/drug effects
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- Signal Transduction/drug effects
- Drug Delivery Systems
- Molecular Targeted Therapy
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors
- ATP Binding Cassette Transporter, Subfamily B/genetics
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Affiliation(s)
- Pablo Álvarez-Carrasco
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
- Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Fernanda Morales-Villamil
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
- Facultad de Medicina, Benemérita Universidad de Puebla, Puebla 72000, Mexico
| | - Carmen Maldonado-Bernal
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico
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Diab M, Hamdi A, Al-Obeidat F, Hafez W, Cherrez-Ojeda I, Gador M, Rashid G, Elkhazin SF, Ibrahim MA, Ismail TF, Alkafaas SS. Discovery of drug transporter inhibitors tied to long noncoding RNA in resistant cancer cells; a computational model -in silico- study. Front Immunol 2025; 16:1511029. [PMID: 40352931 PMCID: PMC12061905 DOI: 10.3389/fimmu.2025.1511029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 03/26/2025] [Indexed: 05/14/2025] Open
Abstract
Chemotherapeutic resistance is a major obstacle to chemotherapeutic failure. Cancer cell resistance involves several mechanisms, including epithelial-to-mesenchymal transition (EMT), signaling pathway bypass, drug efflux activation, and impairment of drug entry. P-glycoproteins (P-gp) are an efflux transporter that pumps chemotherapeutic drugs out of cancer cells, resulting in chemotherapeutic resistance. Several types of long noncoding RNA (lncRNAs) have been identified in resistant cancer cells, including ODRUL, MALAT1, and ANRIL. The high expression level of ODRUL is related to the induction of ATP-binding cassette (ABC) gene expression, resulting in the emergence of doxorubicin resistance in osteosarcoma. lncRNAs are observed to be regulators of drug transporters in cancer cells such as MALAT1 and ANRIL. Targeting P-gp expression using natural products is a new strategy to overcome cancer cell resistance and improve the sensitivity of resistant cells toward chemotherapies. This review validates the inhibitory effects of natural products on P-gp expression and activity using in silico molecular docking. In silico analysis showed that Delphinidin and Asparagoside-f are the most significant natural product inhibitors of p-glycoprotein-1. These inhibitors can reverse multi-drug resistance and induce the sensitivity of resistant cancer cells toward chemotherapy based on in silico molecular docking. It is important to validate that pre-elementary docking can be confirmed using in vitro and in vivo experimental data.
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Affiliation(s)
- Mohanad Diab
- Mediclinic Airport Road Hospital, Abu Dhabi, United Arab Emirates
| | - Amel Hamdi
- Molecular biology and Hematology, Abu Dhabi University, Abu Dhabi, United Arab Emirates
| | - Feras Al-Obeidat
- College of Technological Innovation at Zayed University, Abu Dhabi, United Arab Emirates
| | - Wael Hafez
- NMC Royal Hospital, Abu Dhabi, United Arab Emirates
- Department of Internal Medicine, Medical Research and Clinical Studies Institute, The National Research Center, Cairo, Egypt
| | - Ivan Cherrez-Ojeda
- School of Health, Universidad Espíritu Santo-Ecuador, Samborondón, Guayas, Ecuador
- Respiralab Research Group, Guayaquil, Guayas, Ecuador
| | - Muneir Gador
- NMC Royal Hospital, Abu Dhabi, United Arab Emirates
| | - Gowhar Rashid
- Department of Clinical Biochemistry, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, India
| | - Sana F. Elkhazin
- Mediclinic Airport Road Hospital, Abu Dhabi, United Arab Emirates
| | | | | | - Samar Sami Alkafaas
- Molecular Cell Biology Unit, Division of Biochemistry, Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
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Guo Y, Ashrafizadeh M, Tambuwala MM, Ren J, Orive G, Yu G. P-glycoprotein (P-gp)-driven cancer drug resistance: biological profile, non-coding RNAs, drugs and nanomodulators. Drug Discov Today 2024; 29:104161. [PMID: 39245345 DOI: 10.1016/j.drudis.2024.104161] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 08/07/2024] [Accepted: 09/04/2024] [Indexed: 09/10/2024]
Abstract
Drug resistance has compromised the efficacy of chemotherapy. The dysregulation of drug transporters including P-glycoprotein (P-gp) can mediate drug resistance through drug efflux. In this review, we highlight the role of P-gp in cancer drug resistance and the related molecular pathways, including phosphoinositide 3-kinase (PI3K)-Akt, phosphatase and tensin homolog (PTEN) and nuclear factor-κB (NF-κB), along with non-coding RNAs (ncRNAs). Extracellular vesicles secreted by the cells can transport ncRNAs and other proteins to change P-gp activity in cancer drug resistance. P-gp requires ATP to function, and the induction of mitochondrial dysfunction or inhibition of glutamine metabolism can impair P-gp function, thus increasing chemosensitivity. Phytochemicals, small molecules and nanoparticles have been introduced as P-gp inhibitors to increase drug sensitivity in human cancers.
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Affiliation(s)
- Yang Guo
- Department of Respiratory and Critical Care Medicine, Shenyang Tenth People's Hospital (Shenyang Chest Hospital), No. 11 Beihai Street, Dadong District, Shenyang 110044, Liaoning, China
| | - Milad Ashrafizadeh
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China
| | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, UK
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Gorka Orive
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain; University Institute for Regenerative Medicine and Oral Implantology-UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria-Gasteiz, Spain; Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore 169856, Singapore.
| | - Guiping Yu
- Department of Cardiothoracic Surgery, The Affiliated Jiangyin Hospital of Nantong University, No. 163 Shoushan Road, Jiangyin, China.
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Davodabadi F, Sajjadi SF, Sarhadi M, Mirghasemi S, Nadali Hezaveh M, Khosravi S, Kamali Andani M, Cordani M, Basiri M, Ghavami S. Cancer chemotherapy resistance: Mechanisms and recent breakthrough in targeted drug delivery. Eur J Pharmacol 2023; 958:176013. [PMID: 37633322 DOI: 10.1016/j.ejphar.2023.176013] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 08/28/2023]
Abstract
Conventional chemotherapy, one of the most widely used cancer treatment methods, has serious side effects, and usually results in cancer treatment failure. Drug resistance is one of the primary reasons for this failure. The most significant drawbacks of systemic chemotherapy are rapid clearance from the circulation, the drug's low concentration in the tumor site, and considerable adverse effects outside the tumor. Several ways have been developed to boost neoplasm treatment efficacy and overcome medication resistance. In recent years, targeted drug delivery has become an essential therapeutic application. As more mechanisms of tumor treatment resistance are discovered, nanoparticles (NPs) are designed to target these pathways. Therefore, understanding the limitations and challenges of this technology is critical for nanocarrier evaluation. Nano-drugs have been increasingly employed in medicine, incorporating therapeutic applications for more precise and effective tumor diagnosis, therapy, and targeting. Many benefits of NP-based drug delivery systems in cancer treatment have been proven, including good pharmacokinetics, tumor cell-specific targeting, decreased side effects, and lessened drug resistance. As more mechanisms of tumor treatment resistance are discovered, NPs are designed to target these pathways. At the moment, this innovative technology has the potential to bring fresh insights into cancer therapy. Therefore, understanding the limitations and challenges of this technology is critical for nanocarrier evaluation.
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Affiliation(s)
- Fatemeh Davodabadi
- Department of Biology, Faculty of Basic Science, Payame Noor University, Tehran, Iran.
| | - Seyedeh Fatemeh Sajjadi
- School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran.
| | - Mohammad Sarhadi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Shaghayegh Mirghasemi
- Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran.
| | - Mahdieh Nadali Hezaveh
- Department of Chemical Engineering, Isfahan University of Technology, Isfahan, 84156-83111, Iran.
| | - Samin Khosravi
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran.
| | - Mahdieh Kamali Andani
- Department of Biology, Faculty of Basic Science, Payame Noor University, Tehran, Iran.
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
| | - Mohsen Basiri
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Saeid Ghavami
- Academy of Silesia, Faculty of Medicine, Rolna 43, 40-555. Katowice, Poland; Research Institute of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, MB R3E 3P5, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 3P5, Canada.
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Muacevic A, Adler JR. Long-Term Outcomes of Definitive Chemoradiotherapy for Early-Stage Extranodal Natural Killer/T-cell Lymphoma, Nasal Type: A Retrospective Analysis From a Single Center. Cureus 2023; 15:e34348. [PMID: 36865952 PMCID: PMC9974215 DOI: 10.7759/cureus.34348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2023] [Indexed: 01/30/2023] Open
Abstract
Background Nasal extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare type of lymphoma with characteristic histological features. Although radiotherapy can achieve a high response rate, long-term efficacy and safety are yet to be established. Methodology Using electronic health records, we identified relevant patients treated at our hospital from August 2005 to August 2015. We enrolled patients with pathologically confirmed ENKTL treated with curative intent radiotherapy. Results We included 13 patients who underwent definitive radiotherapy in the analysis, comprising 11 males and 2 females and a median age of 53 years (range: 28-73). The median follow-up period was 113.4 months. The overall survival at 5 and 10 years was 92.3% (95% confidence interval [CI]: 57-99 %) and 68.4% (95% CI: 29-89 %), respectively. The most common radiation-related late-term toxicity was sinus disorder (Grade 1-2) in 11 patients (85%). Radiation-related grade 3 to 5 toxicities were not observed. Conclusion The present retrospective study elucidated the long-term safety and effectiveness of curative intent radiotherapy in patients with localized ENKTL.
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Affiliation(s)
| | - John R Adler
- Radiology, University of Tokyo Hospital, Tokyo, JPN
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Lopatina T, Sarcinella A, Brizzi MF. Tumour Derived Extracellular Vesicles: Challenging Target to Blunt Tumour Immune Evasion. Cancers (Basel) 2022; 14:cancers14164020. [PMID: 36011012 PMCID: PMC9406972 DOI: 10.3390/cancers14164020] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/12/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Tumour onset and development occur because of specific immune support. The immune system, which is originally able to perceive and eliminate incipient cancer cells, becomes suppressed and hijacked by cancer. For these purposes, tumour cells use extracellular vesicles (TEVs). Specific molecular composition allows TEVs to reprogram immune cells towards tumour tolerance. Circulating TEVs move from their site of origin to other organs, preparing “a fertile soil” for metastasis formation. This implies that TEV molecular content can provide a valuable tool for cancer biomarker discovery and potential targets to reshape the immune system into tumour recognition and eradication. Abstract Control of the immune response is crucial for tumour onset and progression. Tumour cells handle the immune reaction by means of secreted factors and extracellular vesicles (EV). Tumour-derived extracellular vesicles (TEV) play key roles in immune reprogramming by delivering their cargo to different immune cells. Tumour-surrounding tissues also contribute to tumour immune editing and evasion, tumour progression, and drug resistance via locally released TEV. Moreover, the increase in circulating TEV has suggested their underpinning role in tumour dissemination. This review brings together data referring to TEV-driven immune regulation and antitumour immune suppression. Attention was also dedicated to TEV-mediated drug resistance.
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Goswamy R, Ajufo H, Maiti A, Brown R, Juneja H, Apostolidou E. Refractory Hydroa Vacciniforme-like Lymphoma: Biological Insights from Morphoproteomic Analysis. Int J Hematol Oncol Stem Cell Res 2022; 16:177-183. [PMID: 36694700 PMCID: PMC9831872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 03/26/2021] [Indexed: 01/26/2023] Open
Abstract
T-cell/natural killer cell lymphoproliferative disorders are rare, associated with poor overall survival, and have limited treatment options. We report a case of a patient who developed hydroa vacciniforme-like lymphoma (HVLL, an EBV-peripheral T-cell lymphoma), refractory to multiple lines of systemic therapy including methotrexate, mycophenolate mofetil, dapsone, thalidomide, prednisone, and romidepsin. We conducted morphoproteomic analysis of the patient's tumor which provided important biological insights. Histopathology showed primarily lymphohistiocytic infiltrates strongly positive EBV expression with a Ki-67 of >50% in the pretreatment biopsy and approximately 90% in the post-treatment biopsy, strong expression of Enhancer of Zester Homolog 2 (EZH2), a constitutively active mTOR pathway, 50% cytoplasmic BCL-2 expression; largely negative PD-1 positive CD8 T-cells. Based on this morphoproteomic analysis and published literature, we postulated that novel agents, including venetoclax, tazemetostat, and other agents may provide a targeted approach for treating HVLL. This case illustrates the use of morphoproteomic analysis to better understand the biology of tumors.
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Affiliation(s)
- Rohit Goswamy
- Department of Internal Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, United States
| | - Helen Ajufo
- Department of Internal Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, United States
| | - Abhishek Maiti
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
| | - Robert Brown
- Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, United States
| | - Harinder Juneja
- Department of Internal Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, United States
| | - Effrosyni Apostolidou
- Department of Internal Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, United States
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8
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Shafiee A, Shamsi S, Kohandel Gargari O, Beiky M, Allahkarami MM, Miyanaji AB, Aghajanian S, Mozhgani SH. EBV associated T- and NK-cell lymphoproliferative diseases: A comprehensive overview of clinical manifestations and novel therapeutic insights. Rev Med Virol 2022; 32:e2328. [PMID: 35122349 DOI: 10.1002/rmv.2328] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/27/2021] [Accepted: 01/13/2022] [Indexed: 11/09/2022]
Abstract
EBV is a ubiquitous virus that infects nearly all people around the world. Most infected people are asymptomatic and do not show serious sequelae, while others may develop Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations characterised by EBV-infected T or NK cells. These disorders are more common in Asian and Latin American people, suggesting genetic predisposition as a contributing factor. The revised WHO classification classifies the lymphoproliferative diseases as: extranodal NK/T-cell lymphoma nasal type (ENKTL), aggressive NK-cell leukemia (ANKL), primary EBV-positive nodal T or NK cell lymphoma (NNKTL), systemic EBV-positive T-cell lymphoproliferative disease of childhood (STCLC), systemic chronic active EBV infection (sys CAEBV), hydroa-vacciniforme (HV) and severe mosquito bite allergy (SMBA). Recent advances in the molecular pathogenesis of these diseases have led to the development of new therapeutic strategies. Due to the infrequency of the diseases and broad clinicopathological overlap, the diagnosis and classification are challenging for both clinicians and pathologists. In this article, we aim to review the recent pathological findings which can be helpful for designing new drugs, clinical presentations and differential diagnoses, and suggested therapeutic interventions to provide a better understanding of these rare disorders.
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Affiliation(s)
- Arman Shafiee
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | - Sahel Shamsi
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Maryam Beiky
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | | | | | - Sepehr Aghajanian
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | - Sayed-Hamidreza Mozhgani
- Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.,Non-communicable Disease Research Center, Alborz University of Medical Sciences, Karaj, Iran
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Song DL, Wang JS, Chen LL, Wang Z. Chronic active Epstein-Barr virus infection treated with PEG-aspargase: A case report. World J Clin Cases 2021; 9:7845-7849. [PMID: 34621836 PMCID: PMC8462253 DOI: 10.12998/wjcc.v9.i26.7845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/08/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic active Epstein-Barr virus infection (EBV) is a systemic EBV-positive lymphoproliferative disease, which may lead to fatal illness. There is currently no standard treatment regimen for chronic active EBV (CAEBV), and hematopoietic stem cell transplantation is the only effective treatment. We here report a CAEBV patient treated with PEG-aspargase, who achieved negative EBV-DNA.
CASE SUMMARY A 33-year-old female Chinese patient who had fever for approximately 3 mo was admitted to our hospital in December 2017. EBV-DNA was positive with a high copy number. She was diagnosed with chronic active EB virus infection. PEG-aspargase was administered at a dose of 1500 U/m2 at a 14-d interval, resulting in eradication of EBV for more than 6 mo. The effect of PEG-aspargase in this patient was excellent.
CONCLUSION A chemotherapy regimen containing PEG-aspargase for CAEBV may be further considered.
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Affiliation(s)
- De-Li Song
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jing-Shi Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Lei-Lei Chen
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Zhao Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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Sadri Nahand J, Rabiei N, Fathazam R, Taghizadieh M, Ebrahimi MS, Mahjoubin-Tehran M, Bannazadeh Baghi H, Khatami A, Abbasi-Kolli M, Mirzaei HR, Rahimian N, Darvish M, Mirzaei H. Oncogenic viruses and chemoresistance: What do we know? Pharmacol Res 2021; 170:105730. [PMID: 34119621 DOI: 10.1016/j.phrs.2021.105730] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022]
Abstract
Chemoresistance is often referred to as a major leading reason for cancer therapy failure, causing cancer relapse and further metastasis. As a result, an urgent need has been raised to reach a full comprehension of chemoresistance-associated molecular pathways, thereby designing new therapy methods. Many of metastatic tumor masses are found to be related with a viral cause. Although combined therapy is perceived as the model role therapy in such cases, chemoresistant features, which is more common in viral carcinogenesis, often get into way of this kind of therapy, minimizing the chance of survival. Some investigations indicate that the infecting virus dominates other leading factors, i.e., genetic alternations and tumor microenvironment, in development of cancer cell chemoresistance. Herein, we have gathered the available evidence on the mechanisms under which oncogenic viruses cause drug-resistance in chemotherapy.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Saeid Ebrahimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - AliReza Khatami
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Maryam Darvish
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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11
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Zhang N, Gao M, Wang Z, Zhang J, Cui W, Li J, Zhu X, Zhang H, Yang DH, Xu X. Curcumin reverses doxorubicin resistance in colon cancer cells at the metabolic level. J Pharm Biomed Anal 2021; 201:114129. [PMID: 34000577 DOI: 10.1016/j.jpba.2021.114129] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 04/30/2021] [Accepted: 05/04/2021] [Indexed: 12/11/2022]
Abstract
Doxorubicin (Dox) is commonly used for the treatment of malignant tumors, including colon cancer. However, the development of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in tumor chemotherapy has seriously reduced the therapeutic efficacy of Dox. Natural product curcumin (Cur) was demonstrated to have a variety of pharmacological effects, such as anti-tumor, anti-oxidation and anti-aging activities. Here, we examined the MDR reversal capability of Cur in drug sensitive-(SW620) and resistant-(SW620/Ad300) colon cancer cells, and elucidated the underlying molecular mechanisms at the metabolic level. It was found that Cur reversed P-gp-mediated resistance in SW620/Ad300 cells by enhancing the Dox-induced cytotoxicity and apoptosis. Further mechanistic studies indicated that Cur inhibited the ATP-dependent transport activity of P-gp, thereby increasing the intra-celluar accumulation of Dox in drug-resistant cells. Metabolomics analysis based on UPLC-MS/MS showed that the MDR phenomenon in SW620/Ad300 cells was closely correlated with the upregulation of spermine and spermidine synthesis and D-glutamine metabolism. Cur significantly inhibited the biosynthesis of spermine and spermidine by decreasing the expression of ornithine decarboxylase (ODC) and suppressed D-glutamine metabolism, which in turn decreased the anti-oxidative stress ability and P-gp transport activity of SW620/Ad300 cells, eventually reversed MDR. These findings indicated the MDR reversal activity and the related mechanism of action of Cur, suggesting that Cur could be a promising MDR reversal agent for cancer treatment.
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Affiliation(s)
- Nan Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Ming Gao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Zihan Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Jingxian Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Weiqi Cui
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Jinjin Li
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Xiaolin Zhu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China
| | - Hang Zhang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
| | - Dong-Hua Yang
- College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, NY, 11439, Jamaica.
| | - Xia Xu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
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12
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Mallal P, Ammanuel B, White R, Kennedy C, Cheah CY. Simultaneous intraocular and cutaneous extranodal NK/T-cell lymphoma refractory to multiple therapies including pembrolizumab. Clin Case Rep 2021; 9:e04194. [PMID: 34026185 PMCID: PMC8133067 DOI: 10.1002/ccr3.4194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 03/23/2021] [Accepted: 04/02/2021] [Indexed: 02/01/2023] Open
Abstract
Floaters or visual disturbance in a patient with ENKL should prompt evaluation for possible vitreoretinal involvement. Lymphoma with ocular involvement should be treated aggressively and in most cases heralds CNS involvement.
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Affiliation(s)
- Peter Mallal
- Department of HaematologySir Charles Gairdner HospitalNedlandsWAAustralia
| | - Benhur Ammanuel
- Department of Anatomical PathologyPathwest Laboratory MedicineNedlandsWAAustralia
| | - Rohen White
- Department of Radiation OncologySir Charles Gairdner HospitalNedlandsWAAustralia
| | | | - Chan Yoon Cheah
- Department of HaematologySir Charles Gairdner HospitalNedlandsWAAustralia
- Department of HaematologyPathwest Laboratory MedicineNedlandsWAAustralia
- Medical SchoolUniversity of Western AustraliaCrawleyWAAustralia
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13
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Chronic Active Epstein-Barr Virus Infection: The Elucidation of the Pathophysiology and the Development of Therapeutic Methods. Microorganisms 2021; 9:microorganisms9010180. [PMID: 33467742 PMCID: PMC7829705 DOI: 10.3390/microorganisms9010180] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 11/17/2022] Open
Abstract
Chronic active Epstein-Barr virus infection (CAEBV) is a disease where Epstein-Barr virus (EBV)-infected T- or NK-cells are activated and proliferate clonally. The symptoms of this dual-faced disease include systemic inflammation and multiple organ failures caused by the invasion of infected cells: inflammation and neoplasm. At present, the only effective treatment strategy to eradicate EBV-infected cells is allogeneic stem cell transplantation. Lately, the investigation into the disease's pathogenic mechanism and pathophysiology has been advancing. In this review, I will evaluate the new definition in the 2017 WHO classification, present the advancements in the study of CAEBV, and unfold the future direction.
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14
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Feng J, Chen Q, Zhang P, Huang X, Xie W, Zhang H, Yao P. Latent Membrane Protein 1 Promotes Tumorigenesis Through Upregulation of PGC1β Signaling Pathway. Stem Cell Rev Rep 2021; 17:1486-1499. [PMID: 33423158 PMCID: PMC8316210 DOI: 10.1007/s12015-020-10112-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2020] [Indexed: 12/01/2022]
Abstract
Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with poor prognosis. In this study, we aimed to investigate the potential mechanism of latent membrane protein 1 (LMP1)-mediated tumorigenesis and provide a novel therapeutic strategy for targeting the EBV DNA genome. We found that LMP1 upregulated the expression of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1β (PGC1β) through activation of nuclear factor-κB (NF-κB). Furthermore, the activated PGC1β upregulated the expression of 8-oxoguanine DNA glycosylase (OGG1) through the coactivation of nuclear respiratory factor 1 (NRF1) and GA-binding protein α (GABPα), preventing reactive oxygen species (ROS)-mediated base incision in the EBV genome and favoring its survival. Interruption of hexokinase domain component 1 (HKDC1) by either shRNA or Tf-D-HKC8 peptide suppressed the interaction of HKDC1 with voltage-dependent anion channel 1 (VDAC1), triggering mitochondrial dysfunction and excessive generation of ROS, thus resulting in EBV suppression through ROS-mediated DNA damage. Suppression of the EBV genome inhibited the expression of the LMP1/PGC1β/HKDC1/OGG1 signaling pathway, forming a positive feed forward loop for the generation of ROS, hence inhibiting the EBV genome and subsequent EBV-associated tumor development. We concluded that LMP1 triggers EBV-associated tumorigenesis through activation of the PGC1β pathway. This study provided a novel therapeutic strategy for the treatment of EBV-associated tumors by targeting HKDC1. ![]()
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Affiliation(s)
- Jia Feng
- Department of Hematology, Peking University Shenzhen Hospital, 518036, Shenzhen, People's Republic of China
| | - Qi Chen
- Department of Hematology, Peking University Shenzhen Hospital, 518036, Shenzhen, People's Republic of China
| | - Ping Zhang
- Department of Hematology, Peking University Shenzhen Hospital, 518036, Shenzhen, People's Republic of China
| | - Xiaodong Huang
- Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, 430060, Wuhan, People's Republic of China
| | - Weiguo Xie
- Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, 430060, Wuhan, People's Republic of China
| | - Hongyu Zhang
- Department of Hematology, Peking University Shenzhen Hospital, 518036, Shenzhen, People's Republic of China.
| | - Paul Yao
- Department of Hematology, Peking University Shenzhen Hospital, 518036, Shenzhen, People's Republic of China.
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15
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Sejic N, George LC, Tierney RJ, Chang C, Kondrashova O, MacKinnon RN, Lan P, Bell AI, Lessene G, Long HM, Strasser A, Shannon-Lowe C, Kelly GL. BCL-XL inhibition by BH3-mimetic drugs induces apoptosis in models of Epstein-Barr virus-associated T/NK-cell lymphoma. Blood Adv 2020; 4:4775-4787. [PMID: 33017468 PMCID: PMC7556124 DOI: 10.1182/bloodadvances.2020002446] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 08/26/2020] [Indexed: 12/15/2022] Open
Abstract
Epstein-Barr virus (EBV)-associated T- and natural killer (NK)-cell malignancies, such as extranodal NK-/T-cell lymphoma (ENKTL), exhibit high chemoresistance and, accordingly, such patients have a poor prognosis. The rare nature of such cancers and nonmalignant T/NK lymphoproliferative disorders, such as chronic active EBV (CAEBV), has limited our understanding of the pathogenesis of these diseases. Here, we characterize a panel of ENKTL- and CAEBV-derived cell lines that had been established from human tumors to be used as preclinical models of these diseases. These cell lines were interleukin-2 dependent and found to carry EBV in a latency II gene-expression pattern. All cell lines demonstrated resistance to cell death induction by DNA damage-inducing agents, the current standard of care for patients with these malignancies. This resistance was not correlated with the function of the multidrug efflux pump, P-glycoprotein. However, apoptotic cell death could be consistently induced following treatment with A-1331852, a BH3-mimetic drug that specifically inhibits the prosurvival protein BCL-XL. A-1331852-induced apoptosis was most efficacious when prosurvival MCL-1 was additionally targeted, either by BH3-mimetics or genetic deletion. Xenograft models established from the ENKTL cell line SNK6 provided evidence that A-1331852 treatment could be therapeutically beneficial in vivo. The data here suggest that therapeutic targeting of BCL-XL would be effective for patients with EBV-driven T/NK proliferative diseases, however, MCL-1 could be a potential resistance factor.
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Affiliation(s)
- Nenad Sejic
- The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
- Institute of Immunology and Immunotherapy and
| | - Lindsay C George
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Rosemary J Tierney
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Catherine Chang
- The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
| | - Olga Kondrashova
- The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Ruth N MacKinnon
- Victorian Cancer Cytogenetics Service, St. Vincent's Hospital Melbourne, Fitzroy, VIC, Australia; and
- Department of Medicine (St. Vincent's) and
| | - Ping Lan
- The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
| | - Andrew I Bell
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Guillaume Lessene
- The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
- Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC, Australia
| | | | - Andreas Strasser
- The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | | | - Gemma L Kelly
- The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
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16
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Liu W, Li Y, Zhao Z, Li X. Clinical relevance of multi-drug resistance gene C3435T polymorphism in diffuse large B-cell lymphoma in Xinjiang. Medicine (Baltimore) 2020; 99:e21704. [PMID: 32871888 PMCID: PMC7458266 DOI: 10.1097/md.0000000000021704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 05/29/2020] [Accepted: 06/30/2020] [Indexed: 10/24/2022] Open
Abstract
To explore the relationship between C3435T polymorphism of multi-drug resistance gene (MDR1) gene and susceptibility, clinicopathological characteristics, curative effect and hematological toxicity of diffuse large B-cell lymphoma (DLBCL) in XinJiang.The peripheral venous blood samples of 54 patients with DLBCL and 60 healthy controls were collected. The alleles and genotypes of MDR1 gene C3435T were detected by DNA direct extraction with PCR technique, and the frequency of C3435T allele and genotypes were detected by the chi-square test. The relationship between the allele and genotype distribution of C3435T locus and the susceptibility, clinicopathological characteristics, curative effect and hematological toxicity of DLBCL were analyzed.1 the frequency of CT heterozygote and CC homozygote mutation was significantly higher in the case group (46.3% in CT genotype and 42.6% in CC genotype) compared to the control group (P < 0.05). The frequency of CC genotype mutation in the case group was 42.6%, which was significantly higher than that in the control group (P < 0.05, OR 3.209, 95% CI: 1.288-7.997). 2 the genotypes of C3435T locus of MDR1 gene were distributed in age, sex, nationality, pathological characteristics, clinical-stage, IPI index, B symptoms, infection with EB virus, clinicopathological characteristics and clinical efficacy of hepatitis B in patients with DLBCL. There was no significant difference in myelosuppression (P > 0.05).The homozygous mutation genotype of CC is the risk genotype of DLBCL. The alleles and genotypes are not associated with the clinicopathological characteristics, efficacy and myelosuppression toxicity of DLBCL.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/genetics
- Adult
- Aged
- Aged, 80 and over
- Alleles
- Case-Control Studies
- China
- Drug Resistance, Neoplasm/genetics
- Female
- Heterozygote
- Homozygote
- Humans
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/pathology
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
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HKDC1 C-terminal based peptides inhibit extranodal natural killer/T-cell lymphoma by modulation of mitochondrial function and EBV suppression. Leukemia 2020; 34:2736-2748. [PMID: 32203147 PMCID: PMC7515829 DOI: 10.1038/s41375-020-0801-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 03/05/2020] [Accepted: 03/10/2020] [Indexed: 11/22/2022]
Abstract
Extranodal nasal-type natural killer/T-cell lymphoma (ENKTL) is an Epstein–Barr virus (EBV) associated lymphoma that progresses rapidly and relapses frequently. Advanced ENKTL is multidrug chemoresistant and has a poor prognosis. In this study, we aim to develop a novel hexokinase domain component 1 (HKDC1)-based antitumor target for ENKTL that is involved with the antimetabolic signaling pathway, EBV replication, and P-glycoprotein (P-gp) expression. We showed that HKDC1 is highly upregulated in ENKTL cells and HKDC1 knockdown significantly suppresses ENKTL tumor growth. In addition, HKDC1 is highly identical with four other hexokinase isoforms, with the only difference being in the last eight amino acids (aa) at the C-terminal. Further investigation showed that peptide delivery of the last eight aa of HKDC1 at the C-terminal (HKC8) with D-configuration using transferrin (Tf) receptor internalization sequence (Tf-D-HKC8) inhibits HKDC1 association with vascular endothelial growth factor 1 (VDAC1), resulting in mitochondrial dysfunction and reactive oxygen species (ROS) overgeneration and subsequently suppressing EBV replication and P-gp expression, making it very effective in killing EBV-positive ENKTL cells. Further in vivo experiments showed that local injection of Tf-D-HKC8 peptide significantly suppresses ENKTL tumor growth and EBV replication in ENKTL xenograft mouse models. We conclude that HKDC1 C-terminal-based peptides inhibit ENKTL by modulation of mitochondrial function and EBV suppression.
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18
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Robinson K, Tiriveedhi V. Perplexing Role of P-Glycoprotein in Tumor Microenvironment. Front Oncol 2020; 10:265. [PMID: 32195185 PMCID: PMC7066112 DOI: 10.3389/fonc.2020.00265] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 02/17/2020] [Indexed: 12/22/2022] Open
Abstract
Development of multidrug resistance (MDR) still remains a major obstacle to the long-term success of cancer therapy. P-glycoprotein (P-gp) is a well-identified membrane transporter with capability to efflux drug molecules out of the cancer cell leading to reduced efficiency of chemotherapy. Cancer cells upregulate P-gp expression as an adaptive response to evade chemotherapy mediated cell death. While several P-gp inhibitors have been discovered by in silico and pre-clinical studies, very few have successfully passed all phases of the clinical trials. Studies show that application of P-gp inhibitors in cancer therapy regimen following development of MDR achieved limited beneficial outcomes. While, the non-specific substrate binding to P-gp has made the drug-design a challenge, a bigger perplexing challenge comes from its role in tumor immunology. Expression of P-gp was noted immune cell phenotypes with apparently antagonistic functionality. Both pro-tumor MΦ2-macrophages and, anti-tumor NK-cell and Th17/CD4+T cell subsets have shown enhanced expression of P-gp. While drug based inhibition of P-gp in pro-tumor immune cell phenotypes could promote tumor elimination, however, it would not be a rational choice to exert inhibition of P-gp on anti-tumor immune cell phenotypes. This mutually exclusive paradigm of P-gp functionality requires a more comprehensive and detailed understanding of its role in tumor microenvironment with active interplay of cancer and immune cells in the tumor mileu. In this review, we focus on the current understanding of the role of P-gp in cancer cells and immune cells and finally attempt to highlight some caveats in the current understanding of its role in comprehensive tumor microenvironment along with challenges in the development of P-gp inhibitors toward anti-cancer therapy.
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Affiliation(s)
- Kianna Robinson
- Department of Biological Sciences, Tennessee State University, Nashville, TN, United States
| | - Venkataswarup Tiriveedhi
- Department of Biological Sciences, Tennessee State University, Nashville, TN, United States.,Department of Pharmacology, Vanderbilt University, Nashville, TN, United States
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19
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Mechanistic Insights into Chemoresistance Mediated by Oncogenic Viruses in Lymphomas. Viruses 2019; 11:v11121161. [PMID: 31888174 PMCID: PMC6950054 DOI: 10.3390/v11121161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/09/2019] [Accepted: 12/12/2019] [Indexed: 12/17/2022] Open
Abstract
Viral lymphomagenesis induced by infection with oncogenic viruses, such as Kaposi’s sarcoma associated herpesvirus (KSHV), Epstein–Barr virus (EBV) and human T-cell leukemia virus (HTLV-1), represents a group of aggressive malignancies with a diverse range of pathological features. Combined chemotherapy remains the standard of care for these virus-associated lymphomas; however, frequent chemoresistance is a barrier to achieving successful long-term disease-free survival. There is increasing evidence that indicates virus-associated lymphomas display more resistance to cytotoxic chemotherapeutic agents than that observed in solid tumors. Although the tumor microenvironment and genetic changes, such as key oncogene mutations, are closely related to chemoresistance, some studies demonstrate that the components of oncogenic viruses themselves play pivotal roles in the multidrug chemoresistance of lymphoma cells. In this review, we summarize recent advances in the understanding of the mechanisms through which oncogenic viruses mediate lymphoma cell chemoresistance, with a particular focus on KSHV and EBV, two major oncogenic viruses. We also discuss the current challenges to overcome these obstacles in the treatment of virus-associated lymphomas.
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20
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Kim SJ, Yoon DH, Kim JS, Kang HJ, Lee HW, Eom HS, Hong JY, Cho J, Ko YH, Huh J, Yang WI, Park WS, Lee SS, Suh C, Kim WS. Efficacy of Brentuximab Vedotin in Relapsed or Refractory High-CD30-Expressing Non-Hodgkin Lymphomas: Results of a Multicenter, Open-Labeled Phase II Trial. Cancer Res Treat 2019; 52:374-387. [PMID: 31476851 PMCID: PMC7176958 DOI: 10.4143/crt.2019.198] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 08/12/2019] [Indexed: 12/28/2022] Open
Abstract
Purpose The treatment outcome of brentuximab vedotin (BV) has not been related with CD30 expression in previous studies enrolling patients with a wide range of CD30 expression level. Thus, this study explored the efficacy of BV in high-CD30–expressing non-Hodgkin lymphoma (NHL) patients most likely to benefit. Materials and Methods This phase II study (Clinicaltrials.gov: NCT02280785) enrolled relapsed or refractory high-CD30–expressing NHL, with BV administered intravenously at 1.8 mg/kg every 3 weeks. The primary endpoint was > 40% disease control rate, consisting of complete response (CR), partial response (PR), or stable disease. We defined high CD30 expression as ≥ 30% tumor cells positive for CD30 by immunohistochemistry. Results High-CD30-expressing NHL patients (n=33) were enrolled except anaplastic large cell lymphoma. The disease control rate was 48.5% (16/33) including six CR and six PR; six patients (4CR, 2PR) maintained their response over 16 completed cycles. Response to BV and survival were not associated with CD30 expression levels. Over a median of 29.2 months of follow-up, the median progression-free and overall survival rates were 1.9 months and 6.1 months, respectively. The most common adverse events were fever (39%), neutropenia (30%), fatigue (24%), and peripheral sensory neuropathy (27%). In a post-hoc analysis for the association of multiple myeloma oncogene 1 (MUM1) on treatment outcome, MUM1-negative patients showed a higher response (55.6%, 5/9) than MUM1-positive patients (13.3%, 2/15). Conclusion BV performance as a single agent was acceptable in terms of disease control rates and toxicity profiles, especially MUM1-negative patients.
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Affiliation(s)
- Seok Jin Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dok Hyun Yoon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Seok Kim
- Division of Hematology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Jin Kang
- Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hye Won Lee
- Center for Hematologic Malignancy, National Cancer Center, Goyang, Korea
| | - Hyeon-Seok Eom
- Center for Hematologic Malignancy, National Cancer Center, Goyang, Korea
| | - Jung Yong Hong
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Junhun Cho
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Hyeh Ko
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jooryung Huh
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Woo-Ick Yang
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Weon Seo Park
- Department of Pathology, National Cancer Center, Goyang, Korea
| | - Seung-Sook Lee
- Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Cheolwon Suh
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Won Seog Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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21
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Nam YS, Im KI, Kim N, Song Y, Lee JS, Jeon YW, Cho SG. Down-regulation of intracellular reactive oxygen species attenuates P-glycoprotein-associated chemoresistance in Epstein-Barr virus-positive NK/T-cell lymphoma. Am J Transl Res 2019; 11:1359-1373. [PMID: 30972167 PMCID: PMC6456522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 01/29/2019] [Indexed: 06/09/2023]
Abstract
Epstein-Barr virus (EBV)-positive extranodal NK/T-cell lymphoma is a rare and highly aggressive disease with a poor prognosis and strong resistance to anti-cancer drugs. Reactive oxygen species (ROS) are closely related to tumorigenesis and P-glycoprotein (P-gp) is highly expressed in various cancers. However, the exact relationship between ROS and P-gp in EBV-positive lymphoma remains unclear. In this study, we demonstrated that EBV latent infection induced intracellular ROS production and increased ROS levels triggered elevated P-gp expression, which resulted in strong resistance to existing anti-cancer drugs in EBV-positive lymphoma cell lines and in patients' tissue samples. We also verified that regulation of intracellular ROS reduced P-gp expression and function via inhibition of STAT1 phosphorylation. These results indicate that treatment with a ROS scavenger is a potential therapeutic strategy to overcome resistance to anti-cancer drugs by downregulating the expression of P-gp in EBV-positive NK/T-cell lymphoma.
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Affiliation(s)
- Young-Sun Nam
- Institute for Translational Research and Molecular Imaging, The Catholic University of Korea, College of MedicineKorea
- Department of Biomedicine and Health Sciences, The Catholic University of Korea, College of MedicineKorea
- Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease (CRCID), Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of MedicineSeoul, Korea
| | - Keon-Il Im
- Institute for Translational Research and Molecular Imaging, The Catholic University of Korea, College of MedicineKorea
- Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease (CRCID), Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of MedicineSeoul, Korea
| | - Nayoun Kim
- Institute for Translational Research and Molecular Imaging, The Catholic University of Korea, College of MedicineKorea
- Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease (CRCID), Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of MedicineSeoul, Korea
| | - Yunejin Song
- Institute for Translational Research and Molecular Imaging, The Catholic University of Korea, College of MedicineKorea
- Department of Biomedicine and Health Sciences, The Catholic University of Korea, College of MedicineKorea
- Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease (CRCID), Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of MedicineSeoul, Korea
| | - Jun-Seok Lee
- Institute for Translational Research and Molecular Imaging, The Catholic University of Korea, College of MedicineKorea
- Department of Biomedicine and Health Sciences, The Catholic University of Korea, College of MedicineKorea
- Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease (CRCID), Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of MedicineSeoul, Korea
| | - Young-Woo Jeon
- Institute for Translational Research and Molecular Imaging, The Catholic University of Korea, College of MedicineKorea
- Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease (CRCID), Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of MedicineSeoul, Korea
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of MedicineSeoul, Korea
| | - Seok-Goo Cho
- Institute for Translational Research and Molecular Imaging, The Catholic University of Korea, College of MedicineKorea
- Department of Biomedicine and Health Sciences, The Catholic University of Korea, College of MedicineKorea
- Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease (CRCID), Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of MedicineSeoul, Korea
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, The Catholic University of Korea, College of MedicineSeoul, Korea
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Shen CL, Huang WH, Hsu HJ, Yang JH, Peng CW. GAP31 from an ancient medicinal plant exhibits anti-viral activity through targeting to Epstein-Barr virus nuclear antigen 1. Antiviral Res 2019; 164:123-130. [PMID: 30817940 DOI: 10.1016/j.antiviral.2019.02.015] [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: 09/25/2018] [Revised: 01/12/2019] [Accepted: 02/22/2019] [Indexed: 11/19/2022]
Abstract
Since it was discovered as the first human tumor virus in 1964, Epstein-Barr Virus (EBV) is now implicated in several types of malignancies. Accordingly, certain aspects of EBV pathobiology have shown promise in anti-cancer research in developing virus-targeting methods for EBV-associated cancers. The unique role of EBV nuclear antigen 1 (EBNA1) in triggering episome-dependent functions has made it as the only latent gene to be expressed in most EBV+ neoplasms. Dimeric EBNA1 binds to the replication origin (oriP) to display its biological impact on EBV-driven cell transformation and maintenance. Hence, EBNA1/oriP has been made an ideal drug target site for anti-EBV protocol development. GAP31 protein was originally isolated from the seeds of an ancient medicinal plant Gelonium multiflorum. Although GAP31 has been shown to exhibit both anti-viral and anti-tumor activity, current understanding of the mechanistic picture underlying GAP31 functioning is not clear. Herein, we identify the EBNA1 DNA-binding domain as a core for GAP31 binding by performing affinity pulldown assays. Recombinant GAP31 (rGAP31) was shown to impair EBNA1-induced dimerization; consequently, it abrogated both EBNA1/oriP-mediated binding and transcription. Importantly, the therapeutic effects of GAP31 showed its capability to abrogate EBV-driven cell transformation and proliferation, and EBV-dependent tumorigenesis in xenograft animal models. Notably, the EBNA1 binding-mutant rGAP31R166A/R169A simply exhibits defective phenotypes in the above-mentioned studies. Our data suggest rGAP31 is a potential anti-viral drug which can be applied to the development of therapeutic strategies against EBV-related malignancies.
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Affiliation(s)
- Chih-Lung Shen
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
| | - Wei-Han Huang
- Department of Oncology and Hematology, Buddhist Hualien Tzu Chi General Hospital, Hualien, Taiwan
| | - Hao-Jen Hsu
- Department of Life Sciences, Tzu Chi University, Hualien, 97004, Taiwan
| | - Jen-Hone Yang
- College of Medicine, Tzu Chi University, Department of Dermatology, Buddhist Hualien Tzu Chi General Hospital, Hualien, Taiwan
| | - Chih-Wen Peng
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan; Department of Life Sciences, Tzu Chi University, Hualien, 97004, Taiwan.
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23
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Hartley G, Elmslie R, Murphy B, Hopkins L, Guth A, Dow S. Cancer stem cell populations in lymphoma in dogs and impact of cytotoxic chemotherapy. Vet Comp Oncol 2018; 17:69-79. [PMID: 30238600 DOI: 10.1111/vco.12447] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 09/11/2018] [Accepted: 09/12/2018] [Indexed: 12/12/2022]
Abstract
Cancer relapse following chemotherapy has been attributed in part to the presence of cancer stem cells (CSC), which drive tumour growth and metastasis and are highly resistant to the effects of cytotoxic chemotherapy. As a result, treatment with cytotoxic chemotherapy selects for drug-resistant CSC populations that eventually drive tumour recurrence. Little is known currently regarding the role of CSC in dogs with lymphoma, nor the impact of chemotherapy on CSC populations. Therefore, we prospectively quantitated CSC populations in dogs with B-cell (BCL) and T-cell lymphoma (TCL), using tumour aspirates and flow cytometric analysis with a panel of CSC markers. In addition, in vitro studies were carried out to determine the impact of chemotherapy resistance on the stem cell phenotype and stem cell properties of lymphoma cells. We found that the percentages of tumour cells expressing CSC markers were significantly increased in dogs with BCL, compared with B cells from normal lymph nodes. Similar findings were observed in dogs with TCL. In vitro studies revealed that lymphoma cells selected for resistance to CHOP chemotherapy had significantly upregulated expression of CSC markers, formed spheroids in culture more readily, and expressed significantly greater aldehyde dehydrogenase activity compared with chemotherapy-sensitive tumour cells. Similar results were observed in tumour samples dogs with relapsed BCL. These findings suggest that cytotoxic chemotherapy can lead to a relative enrichment of tumour cells with CSC properties, which may be associated with lymphoma recurrence.
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Affiliation(s)
- Genevieve Hartley
- Department of Clinical Sciences, Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado
| | - Robyn Elmslie
- Veterinary Specialty and Emergency Hospital, Englewood, Colorado
| | - Brent Murphy
- Department of Clinical Sciences, Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado
| | - Leone Hopkins
- Department of Clinical Sciences, Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado
| | - Amanda Guth
- Department of Clinical Sciences, Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado
| | - Steven Dow
- Department of Clinical Sciences, Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado
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24
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Xiang X, Yuan D, Liu Y, Li J, Wen Q, Kong P, Gao L, Zhang C, Gao L, Peng X, Zhang X. PIM1 overexpression in T-cell lymphomas protects tumor cells from apoptosis and confers doxorubicin resistance by upregulating c-myc expression. Acta Biochim Biophys Sin (Shanghai) 2018; 50:800-806. [PMID: 30020405 DOI: 10.1093/abbs/gmy076] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 06/08/2018] [Indexed: 12/17/2022] Open
Abstract
T-cell lymphomas (TCLs) are a malignancy characterized by tumor aggression and resistance to traditional chemotherapy. Disruption of the extrinsic cell death pathway is essential for resistance to chemotherapy. PIM1 serves as a crucial modulator in cancers. However, the role of PIM1 in TCLs remains unclear. In this study, we studied the roles of PIM1 in established T-lymphoma cell lines Jurkat and HUT-78. CCK-8 assay was conducted to evaluate cell survival and flow cytometry was performed to evaluate cell death of TCL cells. siRNAs were used to knockdown the expression of PIM1 and c-myc. qRT-PCR was used to evaluate the mRNA expression levels of c-myc and PIM1. Western blot analysis was used to evaluate the protein expression levels of PIM1, c-myc, STAT3, and phospho-STAT3. Doxorubicin was used to determine the effect of PIM1 on apoptosis. Our results showed that PIM1 expression was markedly enhanced and induced c-myc expression in TCL cells. Doxorubicin inhibited the expressions of c-myc and PIM1, and triggered the extrinsic cell death of TCLs by suppressing the JAK-STAT3 signaling pathway. Moreover, PIM1 silencing via siRNA suppressed c-myc expression, promoted the cell death of TCLs, and increased doxorubicin sensitivity. Conversely, PIM1 overexpression in TCL cells induced c-myc expression, suppressed TCL cell death, and promoted doxorubicin resistance. Collectively, our results demonstrate that PIM1 overexpression in TCLs participates in cancer cell protection from apoptosis and leads to doxorubicin resistance by inducing c-myc expression, indicating that PIM1 may be a promising target in TCL treatment.
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Affiliation(s)
- Xixi Xiang
- Center of Hematology, the Second Affiliated Hospital of Army Military Medical University, Chongqing, China
| | - Di Yuan
- Department of Educational Technology, Army Medical University, Chongqing, China
| | - Yao Liu
- Center of Hematology, the Second Affiliated Hospital of Army Military Medical University, Chongqing, China
| | - Jiali Li
- Center of Hematology, the Second Affiliated Hospital of Army Military Medical University, Chongqing, China
| | - Qin Wen
- Center of Hematology, the Second Affiliated Hospital of Army Military Medical University, Chongqing, China
| | - Peiyan Kong
- Center of Hematology, the Second Affiliated Hospital of Army Military Medical University, Chongqing, China
| | - Lei Gao
- Center of Hematology, the Second Affiliated Hospital of Army Military Medical University, Chongqing, China
| | - Cheng Zhang
- Center of Hematology, the Second Affiliated Hospital of Army Military Medical University, Chongqing, China
| | - Li Gao
- Center of Hematology, the Second Affiliated Hospital of Army Military Medical University, Chongqing, China
| | - Xiangui Peng
- Center of Hematology, the Second Affiliated Hospital of Army Military Medical University, Chongqing, China
| | - Xi Zhang
- Center of Hematology, the Second Affiliated Hospital of Army Military Medical University, Chongqing, China
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25
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STAT3 is constitutively activated in chronic active Epstein-Barr virus infection and can be a therapeutic target. Oncotarget 2018; 9:31077-31089. [PMID: 30123428 PMCID: PMC6089567 DOI: 10.18632/oncotarget.25780] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 06/22/2018] [Indexed: 12/11/2022] Open
Abstract
Chronic active Epstein-Barr virus infection (CAEBV) is a lymphoproliferative disorder characterized by the clonal proliferation of EBV-infected T or NK cells and is related to severe systemic inflammation. This study aims to investigate STAT3 to elucidate the mechanism underlying the CAEBV development. We determined that STAT3 was constitutively activated in EBV-positive T- or NK-cell lines. We also determined that STAT3 was activated in the peripheral blood mononuclear cells (PBMCs) containing EBV-infected clonally proliferating T or NK cells in six of seven patients with CAEBV. We conducted direct sequencing of the STAT3 Src homology 2 (SH2) domain, which has previously been reported to be mutated in T- or NK-cell neoplasms. No mutation was detected in the STAT3 SH2 domain in patients with CAEBV. Next, we investigated the effects of ruxolitinib, an inhibitor of both JAK1 and JAK2, which phosphorylates and activates STAT3. Ruxolitinib suppressed the phosphorylation of STAT3 in EBV-positive T- or NK-cell lines. Ruxolitinib also decreased the viable cell number of EBV-positive T- or NK-cell lines and PBMCs from patients with CAEBV. Furthermore, ruxolitinib suppressed the production of inflammatory cytokines in the cell lines and CAEBV patient-derived cells. In conclusion, constitutively activated STAT3, which promotes survival and cytokine production, could be a therapeutic target for CAEBV.
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26
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Belmonte C, Ochoa D, Román M, Saiz-Rodríguez M, Wojnicz A, Gómez-Sánchez CI, Martín-Vílchez S, Abad-Santos F. Influence of CYP2D6
,CYP3A4
,CYP3A5
and ABCB1
Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers. Basic Clin Pharmacol Toxicol 2018; 122:596-605. [DOI: 10.1111/bcpt.12960] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 12/29/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Carmen Belmonte
- Clinical Pharmacology Department; Hospital Universitario de la Princesa; Instituto Teofilo Hernando; Instituto de Investigacion Sanitaria Princesa (IP); Madrid Spain
- UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network); Instituto de Investigacion Sanitaria la Princesa (IP); Madrid Spain
| | - Dolores Ochoa
- Clinical Pharmacology Department; Hospital Universitario de la Princesa; Instituto Teofilo Hernando; Instituto de Investigacion Sanitaria Princesa (IP); Madrid Spain
- UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network); Instituto de Investigacion Sanitaria la Princesa (IP); Madrid Spain
| | - Manuel Román
- Clinical Pharmacology Department; Hospital Universitario de la Princesa; Instituto Teofilo Hernando; Instituto de Investigacion Sanitaria Princesa (IP); Madrid Spain
- UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network); Instituto de Investigacion Sanitaria la Princesa (IP); Madrid Spain
| | - Miriam Saiz-Rodríguez
- Clinical Pharmacology Department; Hospital Universitario de la Princesa; Instituto Teofilo Hernando; Instituto de Investigacion Sanitaria Princesa (IP); Madrid Spain
| | - Aneta Wojnicz
- Clinical Pharmacology Department; Hospital Universitario de la Princesa; Instituto Teofilo Hernando; Instituto de Investigacion Sanitaria Princesa (IP); Madrid Spain
| | | | - Samuel Martín-Vílchez
- Clinical Pharmacology Department; Hospital Universitario de la Princesa; Instituto Teofilo Hernando; Instituto de Investigacion Sanitaria Princesa (IP); Madrid Spain
| | - Francisco Abad-Santos
- Clinical Pharmacology Department; Hospital Universitario de la Princesa; Instituto Teofilo Hernando; Instituto de Investigacion Sanitaria Princesa (IP); Madrid Spain
- UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network); Instituto de Investigacion Sanitaria la Princesa (IP); Madrid Spain
- Center for Biomedical Research Network Hepatic and Liver diseases (CIBERedh) - Instituto de Salud Carlos III; Madrid Spain
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27
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Ma M, Yang X, Zhao L, Wang X, Liu L, Jiao W, Wei Y, Shan B. Celecoxib enhances sensitivity to chemotherapy drugs of T-cell lymphoma. Oncol Lett 2018. [PMID: 29541237 DOI: 10.3892/ol.2018.7897] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Celecoxib is a newly-identified nonsteroidal anti-inflammatory drug, which has been used to treat fever in clinical practice. Celecoxib has been demonstrated to suppress the viability of various human tumor cells. However, the effect of celecoxib on response of T-cell lymphoma to chemotherapy agents remains unclear. The aim of the present study was to investigate the effect of celecoxib on chemosensitivity of human T-cell lymphoma, and to address the underlying mechanism of action. The cytotoxicity of CDDP, epirubicin and VCR on Jurkat and Hut-78 cells treated with celecoxib was assessed by MTT assay, and the half-maximal inhibitory concentration (IC50) value was calculated by Origin 75 software. The effect of celecoxib on apoptosis and intracellular concentration of Rhodamine-123 in Jurkat and Hut-78 cells was analyzed by flow cytometry. The expression of transcription factor p65 (p65), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1) at mRNA and protein levels were detected by reverse transcription quantitative polymerase chain reaction and western blotting, respectively. Proliferation suppression rates and apoptosis levels were significantly increased in Jurkat and Hut-78 cells combined with celecoxib compared with those without celecoxib, when treated with CDDP, epirubicin and VCR. The IC50 values of the chemotherapy agents were lower in Jurkat and Hut-78 cells treated with celecoxib compared with those that were not. The apoptosis level, expression of Bax and the intracellular concentration of Rhodamine-123 were increased, whereas the expression of p65, Bcl-2, MDR1 and MRP1 were decreased, in celecoxib-treated Jurkat and Hut-78 cells compared with those without celecoxib treatment. These results indicated that celecoxib may enhance the sensitivity of T-cell lymphoma to chemotherapy drugs by inhibiting the expression of multidrug resistance (MDR)-associated proteins via downregulating the activity of the nuclear factor-κB signaling pathway, suggesting that celecoxib may improve the curative effect of chemotherapy drugs in T-cell lymphoma.
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Affiliation(s)
- Ming Ma
- Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xingxiao Yang
- Department of Infection Management, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Lianmei Zhao
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xuexiao Wang
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Lihua Liu
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Wenjing Jiao
- Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yuanyuan Wei
- Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Baoen Shan
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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28
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Zhou L, Wang H, Li Y. Stimuli-Responsive Nanomedicines for Overcoming Cancer Multidrug Resistance. Theranostics 2018; 8:1059-1074. [PMID: 29463999 PMCID: PMC5817110 DOI: 10.7150/thno.22679] [Citation(s) in RCA: 164] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 11/01/2017] [Indexed: 12/14/2022] Open
Abstract
Chemotherapy is still a main option for cancer therapy, but its efficacy is often unsatisfying due to multidrug resistance (MDR). The tumor microenvironment is considered a dominant factor causing MDR. Stimuli-responsive nanomedicines exhibit many superiorities for reversal of MDR. As smart systems, stimuli-responsive nanomedicines are desirable for achieving site-specific accumulation and triggered drug release in response to slight changes in physicochemical properties in pathological conditions or to exogenous stimuli. In this review, we highlight the current progress of various nanomedicines with different stimuli-responsive capabilities for overcoming MDR. The materials, design, construction as well as efficacy in overcoming MDR of these nanomedicines are discussed. Eventually, we look forward to forthcoming intelligent nanoparticle systems with new mechanisms to deliver drugs for practical applications in conquering cancer MDR.
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Affiliation(s)
- Lei Zhou
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Hao Wang
- China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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29
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Kimura H, Fujiwara S. Overview of EBV-Associated T/NK-Cell Lymphoproliferative Diseases. Front Pediatr 2018; 6:417. [PMID: 30662890 PMCID: PMC6328478 DOI: 10.3389/fped.2018.00417] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 12/14/2018] [Indexed: 01/29/2023] Open
Abstract
Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative diseases (EBV-T/NK-LPDs) are a group of rare diseases resulting from ectopic infection of T or natural killer (NK) lymphocytes with Epstein-Barr virus (EBV). EBV-T/NK-LPDs include chronic active EBV infection, EBV-associated hemophagocytic lymphohistiocytosis, hydroa vacciniforme-like lymphoproliferative disease, and severe mosquito bite allergy. Extra-nodal NK/T-cell lymphoma-nasal type and aggressive NK-cell leukemia can also be included in this broad spectrum. Currently, the etiology of EBV-T/NK-LPDs is unknown and no curative therapy has been established, except for hematopoietic stem cell transplantation. While most cases of EBV-T/NK-LPDs have been documented in specific areas of the world, they have also been documented more broadly across East Asia and Latin America. Consequently, active research and discussion of EBV-T/NK-LPDs are both necessary and important within the extensive international community of scientists and clinicians, to elucidate their etiology and develop a standard therapy.
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Affiliation(s)
- Hiroshi Kimura
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shigeyoshi Fujiwara
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.,Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
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