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1
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Hu X, Li Y, Cao Y, Shi F, Shang L. The role of nitric oxide synthase/ nitric oxide in infection-related cancers: Beyond antimicrobial activity. Biochim Biophys Acta Rev Cancer 2024; 1879:189156. [PMID: 39032540 DOI: 10.1016/j.bbcan.2024.189156] [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: 12/01/2023] [Revised: 07/11/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024]
Abstract
As a free radical and endogenous effector molecule, mammalian endogenous nitric oxide (NO) is mainly derived from nitric oxide synthase (NOS) via L-arginine. NO participates in normal physiological reactions and provides immune responses to prevent the invasion of foreign bacteria. However, NO also has complex and contradictory biological effects. Abnormal NO signaling is involved in the progression of many diseases, such as cancer. In the past decades, cancer research has been closely linked with NOS/ NO, and many tumors with poor prognosis are associated with high expression of NOS. In this review, we give a overview of the biological effects of NOS/ NO. Then we focus on the oncogenic role of iNOS/ NO in HPV, HBV, EBV and H. pylori related tumors. In fact, there is growing evidence that iNOS could be used as a potential therapeutic target in cancer therapy. We emphasize that the pro-tumor effect of NOS/ NO is greater than the anti-tumor effect.
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Affiliation(s)
- Xudong Hu
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Yueshuo Li
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Ya Cao
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Feng Shi
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China; Key Laboratory of Carcinogenesis of National Health Commission, Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - Li Shang
- Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, XiangYa Hospital, Central South University, Changsha 410078, China; Department of Pathology, National Clinical Research Center for Geriatric Disorders/ XiangYa Hospital, Central South University, Changsha 410078, China.
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2
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Bui I, Baritaki S, Libra M, Zaravinos A, Bonavida B. Cancer Resistance Is Mediated by the Upregulation of Several Anti-Apoptotic Gene Products via the Inducible Nitric Oxide Synthase/Nitric Oxide Pathway: Therapeutic Implications. Antioxid Redox Signal 2023; 39:853-889. [PMID: 37466477 DOI: 10.1089/ars.2023.0250] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
Significance: Several therapeutic strategies for cancer treatments have been developed with time, and significant milestones have been achieved recently. However, with these novel therapies, not all cancer types respond and in the responding cancer types only a subset is affected. The failure to respond is principally the result that these cancers develop several mechanisms of resistance. Thus, a focus of current research investigations is to unravel the various mechanisms that regulate resistance and identify suitable targets for new therapeutics. Recent Advances: Hence, many human cancer types have been reported to overexpress the inducible nitric oxide synthase (iNOS) and it has been suggested that iNOS/nitric oxide (NO) plays a pivotal role in the regulation of resistance. We have postulated that iNOS overexpression or NO regulates the overexpression of pivotal anti-apoptotic gene products such as B-cell lymphoma 2 (Bcl-2), B-cell lymphoma extra large (Bcl-xL), myeloid cell leukemia-1 (Mcl-1), and survivin. In this report, we describe the various mechanisms, transcriptional, post-transcriptional, and post-translational, by which iNOS/NO regulates the expression of the above anti-apoptotic gene products. Critical Issues: The iNOS/NO-mediated regulation of the four gene products is not the same with both specific and overlapping pathways. Our findings are, in large part, validated by bioinformatic analyses demonstrating, in several cancers, several direct correlations between the expression of iNOS and each of the four examined anti-apoptotic gene products. Future Directions: We have proposed that targeting iNOS may be highly efficient since it will result in the underexpression of multiple anti-apoptotic proteins and shifting the balance toward the proapoptotic gene products and reversal of resistance. Antioxid. Redox Signal. 39, 853-889.
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Affiliation(s)
- Indy Bui
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA
| | - Stavroula Baritaki
- Laboratory of Experimental Oncology, Department of Surgery, School of Medicine, University of Crete, Heraklion, Greece
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
- Italian League Against Cancer, Catania, Italy
| | - Apostolos Zaravinos
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus
- Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus
| | - Benjamin Bonavida
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA
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3
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Mitochondrial fission factor promotes cisplatin resistancein hepatocellular carcinoma. Acta Biochim Biophys Sin (Shanghai) 2022; 54:301-310. [PMID: 35538029 PMCID: PMC9828151 DOI: 10.3724/abbs.2022007] [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] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and one of the leading causes of cancer-related death worldwide. Chemotherapeutic agents/regimens such as cisplatin (DDP) are frequently used for advanced HCC treatment. However, drug resistance remains a major hindrance and the underline mechanisms are not fully understood. In this study, we investigated the expression pattern and function of mitochondrial fission factor (Mff) in cisplatin-resistant HCC. We found that Mff is highly expressed in cisplatin-resistant HCC tissues and cell lines. Knockdown of Mff suppresses cell proliferation and promotes cell apoptosis of HCC/DDP cells. In addition, knockdown of Mff sensitizes Huh-7/DDP cells to cisplatin treatment, inhibits cell proliferation, migration and invasion, and enhances cell apoptosis. Confocal imaging showed that knockdown of Mff inhibits the mitochondrial fission and downregulates the expression of GTPase dynamin-related protein 1 (Drp1) in cisplatin-resistant Huh-7/DDP cells. Moreover, xenograft tumor model revealed that knockdown of Mff sensitizes Huh-7/DDP xenograft tumor to cisplatin treatment . In summary, our findings suggest that Mff regulates mitochondrial Drp1 expression and promotes cisplatin resistance in HCC, which provides a potential therapeutic target for the treatment of resistant HCC.
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4
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Advances in understanding the role of P-gp in doxorubicin resistance: Molecular pathways, therapeutic strategies, and prospects. Drug Discov Today 2021; 27:436-455. [PMID: 34624510 DOI: 10.1016/j.drudis.2021.09.020] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 07/22/2021] [Accepted: 09/29/2021] [Indexed: 12/11/2022]
Abstract
P-glycoprotein (P-gp) is a drug efflux transporter that triggers doxorubicin (DOX) resistance. In this review, we highlight the molecular avenues regulating P-gp, such as Nrf2, HIF-1α, miRNAs, and long noncoding (lnc)RNAs, to reveal their participation in DOX resistance. These antitumor compounds and genetic tools synergistically reduce P-gp expression. Furthermore, ATP depletion impairs P-gp activity to enhance the antitumor activity of DOX. Nanoarchitectures, including liposomes, micelles, polymeric nanoparticles (NPs), and solid lipid nanocarriers, have been developed for the co-delivery of DOX with anticancer compounds and genes enhancing DOX cytotoxicity. Surface modification of nanocarriers, for instance with hyaluronic acid (HA), can promote selectivity toward cancer cells. We discuss these aspects with a focus on P-gp expression and activity.
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5
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Liang X, Zhou R, Li Y, Yang L, Su M, Lai KP. Clinical characterization and therapeutic targets of vitamin A in patients with hepatocholangiocarcinoma and coronavirus disease. Aging (Albany NY) 2021; 13:15785-15800. [PMID: 34176789 PMCID: PMC8266307 DOI: 10.18632/aging.203220] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 06/04/2021] [Indexed: 02/07/2023]
Abstract
Recent reports indicate that patients with hepatocholangiocarcinoma (CHOL) have a higher morbidity and mortality rate for coronavirus disease (COVID-19). Anti-CHOL/COVID-19 medicines are inexistent. Vitamin A (VA) refers to a potent nutrient with anti-cytotoxic and anti-inflammatory actions. Therefore, this study aimed to determine the potential functions and molecular mechanisms of VA as a potential treatment for patients with both CHOL and COVID-19 (CHOL/COVID-19). The transcriptome data of CHOL patients were obtained from the Cancer Genome Analysis database. Furthermore, the network pharmacology approach and bioinformatics analysis were used to identify and reveal the molecular functions, therapeutic biotargets, and signaling of VA against CHOL/COVID-19. First, clinical findings identified the medical characteristics of CHOL patients with COVID-19, such as susceptibility gene, prognosis, recurrence, and survival rate. Anti-viral and anti-inflammatory pathways, and immunopotentiation were found as potential targets of VA against CHOL/COVID-19. These findings illustrated that VA may contribute to the clinical management of CHOL/COVID-19 achieved by induction of cell repair, suppression of oxidative stress and inflammatory reaction, and amelioration of immunity. Nine vital therapeutic targets (BRD2, NOS2, GPT, MAPK1, CXCR3, ICAM1, CDK4, CAT, and TMPRSS13) of VA against CHOL/COVID-19 were identified. For the first time, the potential pharmacological biotargets, function, and mechanism of action of VA in CHOL/COVID-19 were elucidated.
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Affiliation(s)
- Xiao Liang
- Laboratory of Environmental Pollution and Integrative Omics, Guilin Medical University, Guilin, Guangxi, China.,Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
| | - Rui Zhou
- Department of Hepatobiliary Surgery, Guigang City People's Hospital, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi, China
| | - Yu Li
- Laboratory of Environmental Pollution and Integrative Omics, Guilin Medical University, Guilin, Guangxi, China.,Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
| | - Lu Yang
- Laboratory of Environmental Pollution and Integrative Omics, Guilin Medical University, Guilin, Guangxi, China.,Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
| | - Min Su
- Laboratory of Environmental Pollution and Integrative Omics, Guilin Medical University, Guilin, Guangxi, China.,Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
| | - Keng Po Lai
- Laboratory of Environmental Pollution and Integrative Omics, Guilin Medical University, Guilin, Guangxi, China.,Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
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6
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Ding Y, Fan J, Fan Z, Zhang K. γ-Tocotrienol reverses multidrug resistance of breast cancer cells through the regulation of the γ-Tocotrienol-NF-κB-P-gp axis. J Steroid Biochem Mol Biol 2021; 209:105835. [PMID: 33556581 DOI: 10.1016/j.jsbmb.2021.105835] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/17/2021] [Accepted: 02/03/2021] [Indexed: 02/07/2023]
Abstract
The problem of multidrug resistance (MDR) presents a major obstacle in the chemotherapy of cancer. The MDR phenotype is often linked to the overexpression of ATP-binding cassette (ABC) transporters, that pumps out and decreased intracellular drug accumulation. γ-Tocotrienol, an unsaturated tocopherol belonging to the vitamin E family, has been shown to reverse the MDR of MCF-7/Adr cell. To reveal the role of γ-tocotrienol-NF-κB-P-gp axis in the reversal process, the expression level of mdr1/P-gp was determined by real-time PCR and western blot, while NF-κB activity was detected by immunofluorescence and NF-κB transcriptional activity reporter assay. Besides, mdr1 promoter activity and P-gp transport capacity were measured with the effect of γ-tocotrienol and NF-κB agonist/antagonist. Results showed that γ-tocotrienol effectively inhibited the expression levels of mdr1 mRNA and P-gp protein. It is demonstrated that γ-tocotrienol also suppressed mdr1 promoter activity and the efflux activity of P-gp. In addition, the activation of NF-κB signaling pathway and the transcriptional activity of NF-κB were both reduced by γ-tocotrienol. Evidences also showed that the NF-κB pathway is really involved in the regulation of the expression and function of mdr1/P-gp. Taken together, we confirmed that γ-tocotrienol reversed the MDR of MCF-7/Adr through the signaling pathway of NF-κB and P-gp.
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Affiliation(s)
- Yuedi Ding
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
| | - Jun Fan
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China
| | - Zhenqiang Fan
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China
| | - Kai Zhang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
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7
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Deng Y, Jia F, Chen X, Jin Q, Ji J. ATP Suppression by pH-Activated Mitochondria-Targeted Delivery of Nitric Oxide Nanoplatform for Drug Resistance Reversal and Metastasis Inhibition. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2020; 16:e2001747. [PMID: 32378343 DOI: 10.1002/smll.202001747] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/05/2020] [Accepted: 04/08/2020] [Indexed: 06/11/2023]
Abstract
Mitochondria, which are important mediators for cancer initiation, growth, metastasis, and drug resistance, have been considered as a major target in cancer therapy. Herein, an acid-activated mitochondria-targeted drug nanocarrier is constructed for precise delivery of nitric oxide (NO) as an adenosine triphosphate (ATP) suppressor to amplify the therapeutic efficacy in cancer treatments. By combining α-cyclodextrin (α-CD) and acid-cleavable dimethylmaleic anhydride modified PEG conjugated mitochondria-targeting peptide, the nanocarrier shows prolonged blood circulation time and enhanced cellular uptake together with selectively restoring mitochondria-targeting capability under tumor extracellular pH (6.5). Such specific mitochondria-targeted delivery of NO proves crucial in inducing mitochondria dysfunction through facilitating mitochondrial membrane permeabilization and downregulating ATP level, which can inhibit P-glycoprotein-related bioactivities and formation of tumor-derived microvesicles to combat drug resistance and cancer metastasis. Therefore, this pioneering acid-activated mitochondria-targeted NO nanocarrier is supposed to be a malignant tumor opponent and may provide insights for diverse NO-relevant cancer treatments.
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Affiliation(s)
- Yongyan Deng
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, P. R. China
| | - Fan Jia
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, P. R. China
| | - Xiaohui Chen
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, P. R. China
| | - Qiao Jin
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, P. R. China
| | - Jian Ji
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, P. R. China
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8
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Models for Understanding Resistance to Chemotherapy in Liver Cancer. Cancers (Basel) 2019; 11:cancers11111677. [PMID: 31671735 PMCID: PMC6896032 DOI: 10.3390/cancers11111677] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 12/19/2022] Open
Abstract
The lack of response to pharmacological treatment constitutes a substantial limitation in the handling of patients with primary liver cancers (PLCs). The existence of active mechanisms of chemoresistance (MOCs) in hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma hampers the usefulness of chemotherapy. A better understanding of MOCs is needed to develop strategies able to overcome drug refractoriness in PLCs. With this aim, several experimental models are commonly used. These include in vitro cell-free assays using subcellular systems; studies with primary cell cultures; cancer cell lines or heterologous expression systems; multicellular models, such as spheroids and organoids; and a variety of in vivo models in rodents, such as subcutaneous and orthotopic tumor xenografts or chemically or genetically induced liver carcinogenesis. Novel methods to perform programmed genomic edition and more efficient techniques to isolate circulating microvesicles offer new opportunities for establishing useful experimental tools for understanding the resistance to chemotherapy in PLCs. In the present review, using three criteria for information organization: (1) level of research; (2) type of MOC; and (3) type of PLC, we have summarized the advantages and limitations of the armamentarium available in the field of pharmacological investigation of PLC chemoresistance.
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9
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Najafi M, Salehi E, Farhood B, Nashtaei MS, Hashemi Goradel N, Khanlarkhani N, Namjoo Z, Mortezaee K. Adjuvant chemotherapy with melatonin for targeting human cancers: A review. J Cell Physiol 2018; 234:2356-2372. [PMID: 30192001 DOI: 10.1002/jcp.27259] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 07/20/2018] [Indexed: 12/26/2022]
Abstract
Melatonin is a multifunctional hormone that has long been known for its antitumoral effects. An advantage of the application of melatonin in cancer therapy is its ability to differentially influence tumors from normal cells. In this review, the roles of melatonin adjuvant therapy in human cancer are discussed. Combination of melatonin with chemotherapy could provide synergistic antitumoral outcomes and resolve drug resistance in affected patients. This combination reduces the dosage for chemotherapeutic agents with the subsequent attenuation of side effects related to these drugs on normal cells around tumor and on healthy organs. The combination therapy increases the rate of survival and improves the quality of life in affected patients. Cancer cell viability is reduced after application of the combinational melatonin therapy. Melatonin does all these functions by adjusting the signals involved in cancer progression, re-establishing the dark/light circadian rhythm, and disrupting the redox system for cancer cells. To achieve effective therapeutic outcomes, melatonin concentration along with the time of incubation for this indoleamine needs to be adjusted. Importantly, a special focus is required to be made on choosing an appropriate chemotherapy agent for using in combination with melatonin. Because of different sensitivities of cancer cells for melatonin combination therapy, cancer-specific targeted therapy is also needed to be considered. For this review, the PubMed database was searched for relevant articles based on the quality of journals, the novelty of articles published by the journals, and the number of citations per year focusing only on human cancers.
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Affiliation(s)
- Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Eniseh Salehi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Farhood
- Departments of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Shabani Nashtaei
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Infertility Department, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Khanlarkhani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Namjoo
- Department of Anatomy and Pathology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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10
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Yi YJ, Jia XH, Zhu C, Wang JY, Chen JR, Wang H, Li YJ. Solanine reverses multidrug resistance in human myelogenous leukemia K562/ADM cells by downregulating MRP1 expression. Oncol Lett 2018; 15:10070-10076. [PMID: 29928376 DOI: 10.3892/ol.2018.8563] [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: 08/07/2015] [Accepted: 11/03/2016] [Indexed: 12/15/2022] Open
Abstract
Multidrug resistance (MDR) in leukemia cells is a major obstacle to chemotherapeutic treatment. High expression and constitutive activation of multidrug resistance protein 1 (MRP1) has been associated with the development of resistance to anticancer drugs in a number of tumor types. The activity of c-Jun N-terminal kinase 1 (JNK1) is associated with the occurrence of MDR and MRP1 expression. The present study aimed to investigate the ability of solanine to resensitize the Adriamycin® (ADR)-resistant human myelogenous leukemia cell line K562/ADM to ADR. Results of the Cell Counting Kit-8 assay demonstrated that solanine inhibited K562/ADM cell proliferation. K562/ADM cell sensitivity to ADR was increased following treatment with solanine, indicated by increased intracellular accumulation of ADR. Western blotting demonstrated that treatment with solanine led to reduced MRP1 protein expression, suggesting that solanine-induced ADR accumulation is due to the downregulation of MRP1 expression. Solanine-mediated MRP1 downregulation was observed to be dependent on the JNK signaling pathway. In conclusion, the results of the present study suggest that solanine reverses MDR in K562/ADM cells and may represent a novel therapeutic agent for the treatment of human myelogenous leukemia.
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Affiliation(s)
- Ying-Jie Yi
- Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Xiu-Hong Jia
- Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Cong Zhu
- Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Jian-Yong Wang
- Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Jie-Ru Chen
- Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Hong Wang
- Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - You-Jie Li
- Department of Biochemistry and Molecular Biology, Key Laboratory of Tumor Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
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11
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Mortezaee K. Human hepatocellular carcinoma: Protection by melatonin. J Cell Physiol 2018; 233:6486-6508. [DOI: 10.1002/jcp.26586] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 03/08/2018] [Indexed: 12/12/2022]
Affiliation(s)
- Keywan Mortezaee
- Department of Anatomy, School of Medicine Kurdistan University of Medical Sciences Sanandaj Iran
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12
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Tengan CH, Moraes CT. NO control of mitochondrial function in normal and transformed cells. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2017; 1858:573-581. [PMID: 28216426 PMCID: PMC5487294 DOI: 10.1016/j.bbabio.2017.02.009] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 01/19/2017] [Accepted: 02/15/2017] [Indexed: 10/25/2022]
Abstract
Nitric oxide (NO) is a signaling molecule with multiple facets and involved in numerous pathological process, including cancer. Among the different pathways where NO has a functionally relevant participation, is the control of mitochondrial respiration and biogenesis. NO is able to inhibit the electron transport chain, mainly at Complex IV, regulating oxygen consumption and ATP generation, but at the same time, can also induce increase in reactive oxygen and nitrogen species. The presence of reactive species can induce oxidative damage or participate in redox signaling. In this review, we discuss how NO affects mitochondrial respiration and mitochondrial biogenesis, and how it influences the development of mitochondrial deficiency and cancer. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
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Affiliation(s)
- Celia H Tengan
- Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Universidade Federal de São Paulo, R. Pedro de Toledo, 781, setimo andar, frente, 04039-032, São Paulo, SP, Brazil.
| | - Carlos T Moraes
- University of Miami Miller School of Medicine, Dept. of Neurology and Cell Biology, 1420 NW 9th Avenue, Rm.229, Miami, FL 33136, USA.
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13
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Xu HB, Fu J, Huang F, Yu J. Guggulsterone sensitized drug-resistant human hepatocarcinoma cells to doxorubicin through a Cox-2/P-gp dependent pathway. Eur J Pharmacol 2017; 803:57-64. [PMID: 28342979 DOI: 10.1016/j.ejphar.2017.03.045] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 03/16/2017] [Accepted: 03/21/2017] [Indexed: 01/24/2023]
Abstract
Previous researches indicated that cyclooxygenase-2 (Cox-2) might be involved in P-glycoprotein (P-gp)-mediated multidrug resistance in hepatocellular carcinoma cells. Doxorubicin-resistant hepatocellular carcinoma PLC/PRF/5 cells (PLC/PRF/5R) and HepG2 (HepG2R) cells were developed in the present study. The modulatory effect of guggulsterone on Cox-2 and P-gp in PLC/PRF/5R and HepG2R cells was investigated. Cells proliferation, Cox-2 and P-gp expression, and prostaglandin E2 release were examined using MTT, flow cytometry, western blot and ELISA assays. Small interfering RNA (siRNA) targeted against Cox-2 and multidrug resistance protein (Mdr-1) was used to regulate the expression of Cox-2 and P-gp. The results showed that co-administration of guggulsterone resulted in a significant increase in chemo-sensitivity of PLC/PRF/5R cells to doxorubicin, as compared with doxorubicin treatment alone. When doxorubicin (10µM) was combined with guggulsterone (50µM), the mean apoptotic population of PLC/PRF/5R cells was 20.16%. It was increased by 1.5 times, as compared with doxorubicin (10µM) treatment alone. Furthermore, guggulsterone had significantly inhibitory effect on the levels of Cox-2, P-gp and prostaglandin E2. However, guggulsterone did not show significantly inhibitory effect on the expression of prostaglandin E receptors. In addition, Cox-2 siRNA simultaneously reduced the expression of Cox-2 and P-gp in PLC/PRF/5R cells. Mdr-1 siRNA had no influence on Cox-2, but inhibited P-gp expression. The present study suggested that guggulsterone might enhance the cytotoxic effect of doxorubicin to PLC/PRF/5R cells through a Cox-2/P-gp dependent pathway.
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Affiliation(s)
- Hong-Bin Xu
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 200072 Shanghai, China.
| | - Jun Fu
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 200072 Shanghai, China
| | - Fang Huang
- Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 200072 Shanghai, China
| | - Jing Yu
- Department of Scientific Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
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14
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Wu W, Yang JL, Wang YL, Wang H, Yao M, Wang L, Gu JJ, Cai Y, Shi Y, Yao DF. Reversal of multidrug resistance of hepatocellular carcinoma cells by metformin through inhibiting NF-κB gene transcription. World J Hepatol 2016; 8:985-993. [PMID: 27621764 PMCID: PMC4990762 DOI: 10.4254/wjh.v8.i23.985] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 05/25/2016] [Accepted: 06/14/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To interfere with the activation of nuclear factor-κB (NF-κB) with metformin and explore its effect in reversing multidrug resistance (MDR) of hepatocellular carcinoma (HCC) cells. METHODS Expression of P-glycoprotein (P-gp) and NF-κB in human HepG2 or HepG2/adriamycin (ADM) cells treated with pCMV-NF-κB-small interference RNA (siRNA) with or without metformin, was analyzed by Western blot or fluorescence quantitative PCR. Cell viability was tested by CCK-8 assay. Cell cycle and apoptosis were measured by flow cytometry and Annexin-V-PE/7-AnnexinV apoptosis detection double staining assay, respectively. RESULTS P-gp overexpression in HepG2 and HepG2/ADM cells was closely related to mdr1 mRNA (3.310 ± 0.154) and NF-κB mRNA (2.580 ± 0.040) expression. NF-κB gene transcription was inhibited by specific siRNA with significant down-regulation of P-gp and enhanced HCC cell chemosensitivity to doxorubicin. After pretreatment with metformin, HepG2/ADM cells were sensitized to doxorubicin and P-gp was decreased through the NF-κB signaling pathway. The synergistic effect of metformin and NF-κB siRNA were found in HepG2/ADM cells with regard to proliferation inhibition, cell cycle arrest and inducing cell apoptosis. CONCLUSION Metformin via silencing NF-κB signaling could effectively reverse MDR of HCC cells by down-regulating MDR1/P-gp expression.
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Affiliation(s)
- Wei Wu
- Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Jun-Ling Yang
- Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yi-Lang Wang
- Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Han Wang
- Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Min Yao
- Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Li Wang
- Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Juan-Juan Gu
- Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yin Cai
- Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yun Shi
- Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Deng-Fu Yao
- Wei Wu, Jun-Ling Yang, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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15
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Yi YJ, Jia XH, Wang JY, Li YJ, Wang H, Xie SY. Knockdown of HOXA10 reverses the multidrug resistance of human chronic mylogenous leukemia K562/ADM cells by downregulating P-gp and MRP-1. Int J Mol Med 2016; 37:1405-11. [PMID: 27035504 DOI: 10.3892/ijmm.2016.2539] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 03/16/2016] [Indexed: 11/05/2022] Open
Abstract
Multidrug resistance (MDR) of leukemia cells is a major obstacle in chemotherapeutic treatment. The high expression and constitutive activation of P-glycoprotein (P-gp) and multidrug resistance protein-1 (MRP-1) have been reported to play a vital role in enhancing cell resistance to anticancer drugs in many tumors. The present study aimed to investigate the reversal of MDR by silencing homeobox A10 (HOXA10) in adriamycin (ADR)-resistant human chronic myelogenous leukemia (CML) K562/ADM cells by modulating the expression of P-gp and MRP-1. K562/ADM cells were stably transfected with HOXA10-targeted short hairpin RNA (shRNA). The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis showed that the mRNA and protein expression of HOXA10 was markedly suppressed following transfection with a shRNA-containing vector. The sensitivity of the K562/ADM cells to ADR was enhanced by the silencing of HOXA10, due to the increased intracellular accumulation of ADR. The accumulation of ADR induced by the silencing of HOXA10 may be due to the downregulation of P-gp and MRP-1. Western blot analysis revealed that downregulating HOXA10 inhibited the protein expression of P-gp and MRP-1. Taken together, these results suggest that knockdown of HOXA10 combats resistance and that HOXA10 is a potential target for resistant human CML.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/genetics
- Cell Line, Tumor
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm/genetics
- Gene Expression Regulation, Leukemic
- Gene Knockdown Techniques
- Homeobox A10 Proteins
- Homeodomain Proteins/genetics
- Humans
- K562 Cells
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Multidrug Resistance-Associated Proteins/genetics
- RNA Interference
- RNA, Small Interfering/genetics
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Affiliation(s)
- Ying-Jie Yi
- Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Xiu-Hong Jia
- Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Jian-Yong Wang
- Department of Pediatrics, Yantai Yuhuangding Hospital, Yantai, Shangdong 264000, P.R. China
| | - You-Jie Li
- Department of Biochemistry and Molecular Biology, Key Laboratory of Tumour Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Hong Wang
- Department of Pediatrics, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Shu-Yang Xie
- Department of Biochemistry and Molecular Biology, Key Laboratory of Tumour Molecular Biology, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
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