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Zeng M, Wang Y, Tao X, Fan T, Yin X, Shen C, Wang X. Novel Perspectives in the Management of Colorectal Cancer: Mechanistic Investigations Into the Reversal of Drug Resistance via Active Constituents Derived From Herbal Medicine. Phytother Res 2024; 38:5962-5984. [PMID: 39462152 DOI: 10.1002/ptr.8363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 09/03/2024] [Accepted: 10/05/2024] [Indexed: 10/29/2024]
Abstract
The high incidence and mortality rate of colorectal cancer have become a significant global health burden. Chemotherapy has been the traditional treatment for colorectal cancer and has demonstrated promising antitumor effects, leading to significant improvements in patient survival. However, the development of chemoresistance poses a major challenge during chemotherapy in colorectal cancer, significantly impeding treatment efficacy and affecting patient prognosis. Despite the development of a variety of novel anticolorectal cancer chemotherapy agents, their effectiveness and side effects vary, possibly due to the complex mechanisms of resistance in colorectal cancer. Abnormal drug metabolism or protein targets are the most direct causes of resistance. Further studies have revealed that these resistance mechanisms involve biochemical processes such as altered protein expression, autophagy, and epithelial-mesenchymal transitions. Herbal active ingredients offer an alternative treatment option and have shown promise in reversing colorectal cancer drug resistance. This paper aims to summarize the role of various biochemical processes and key protein targets in the occurrence and maintenance of resistance mechanisms in colorectal cancer. Additionally, it elaborates on the mechanisms of action of herbal active ingredients in reversing colorectal cancer drug resistance. The article also discusses the limitations and opportunities in developing novel anticolorectal cancer drugs based on herbal medicine.
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Affiliation(s)
- Mingtang Zeng
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Yao Wang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Xuelin Tao
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Tianfei Fan
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Xi Yin
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Chao Shen
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Xueyan Wang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
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Hu M, Li J, Fu Y, Xu E, Li D, Huang S, Tong D, Jin S, Guan T, Liu Y. Establishment and characterization of cisplatin-resistant cell lines from canine mammary gland tumors. Theriogenology 2024; 217:103-112. [PMID: 38271764 DOI: 10.1016/j.theriogenology.2024.01.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 01/27/2024]
Abstract
The development of cisplatin resistance is one of the major causes of mammary cancer treatment failure, and is associated with changes in Sox4 gene expression. To investigate the characteristic changes that occur in canine mammary gland tumor (CMGT) cells following the development of acquired cisplatin resistance, along with the relationship between these changes and the Sox4 gene. We constructed cisplatin-resistant cell line, CHMpCIS, from the cell line CHMp, which was isolated from the primary lesion of a malignant CMGT. The biological characteristics of these cells were examined by Western blot analysis, Transwell assays, and mammosphere formation assays. Compared to CHMp cells, CHMpCIS cells exhibited elevated cisplatin resistance, apoptotic escape ability, enhanced epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) features, in addition to over-activation of the Wnt/β-catenin signaling pathway and increased Sox4 protein. In CMGT cases, CMGT tissues (CMGTT) expressed higher levels of Sox4 protein and mRNA compared to adjacent tissues (CAMGTT). We found that these changes were inhibited by silencing of Sox4 expression in CHMpCIS cells. Furthermore, activation of the Wnt/β-catenin signaling pathway increased Sox4 expression levels through a positive feedback loop. These results suggested that CHMpCIS cells circumvented the damage caused by cisplatin through altering the expression of the Sox4 gene and activating the Wnt/β-catenin pathway, thereby changing the cellular biological characteristics.
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Affiliation(s)
- Mengxin Hu
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China; Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Jie Li
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Yunwei Fu
- University Hospital, Northeast Agricultural University, Harbin, 150030, China
| | - Enshuang Xu
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China; Department of Veterinary Surgery, College of Veterinary Medicine, Heilongjiang Bayi Land Reclamation University, Daqing, 163000, China
| | - Ding Li
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Siqi Huang
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Danning Tong
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Shengzi Jin
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Tongxu Guan
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Yun Liu
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China.
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Dhakne P, Pillai M, Mishra S, Chatterjee B, Tekade RK, Sengupta P. Refinement of safety and efficacy of anti-cancer chemotherapeutics by tailoring their site-specific intracellular bioavailability through transporter modulation. Biochim Biophys Acta Rev Cancer 2023; 1878:188906. [PMID: 37172652 DOI: 10.1016/j.bbcan.2023.188906] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/20/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023]
Abstract
Low intracellular bioavailability, off-site toxicities, and multi drug resistance (MDR) are the major constraints involved in cancer chemotherapy. Many anticancer molecules fail to become a good lead in drug discovery because of their poor site-specific bioavailability. Concentration of a molecule at target sites is largely varied because of the wavering expression of transporters. Recent anticancer drug discovery strategies are paying high attention to enhance target site bioavailability by modulating drug transporters. The level of genetic expression of transporters is an important determinant to understand their ability to facilitate drug transport across the cellular membrane. Solid carrier (SLC) transporters are the major influx transporters involved in the transportation of most anti-cancer drugs. In contrast, ATP-binding cassette (ABC) superfamily is the most studied class of efflux transporters concerning cancer and is significantly involved in efflux of chemotherapeutics resulting in MDR. Balancing SLC and ABC transporters is essential to avoid therapeutic failure and minimize MDR in chemotherapy. Unfortunately, comprehensive literature on the possible approaches of tailoring site-specific bioavailability of anticancer drugs through transporter modulation is not available till date. This review critically discussed the role of different specific transporter proteins in deciding the intracellular bioavailability of anticancer molecules. Different strategies for reversal of MDR in chemotherapy by incorporation of chemosensitizers have been proposed in this review. Targeted strategies for administration of the chemotherapeutics to the intracellular site of action through clinically relevant transporters employing newer nanotechnology-based formulation platforms have been explained. The discussion embedded in this review is timely considering the current need of addressing the ambiguity observed in pharmacokinetic and clinical outcomes of the chemotherapeutics in anti-cancer treatment regimens.
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Affiliation(s)
- Pooja Dhakne
- National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India
| | - Megha Pillai
- National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India
| | - Sonam Mishra
- National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India
| | - Bappaditya Chatterjee
- SVKM's NMIMS School of Pharmacy and Management, Department of Pharmaceutics, Vaikunthlal Mehta Road, Vile Parle West, Mumbai, Maharashtra 400056, India
| | - Rakesh K Tekade
- National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India
| | - Pinaki Sengupta
- National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), An Institute of National Importance, Government of India, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Opp. Airforce Station, Palaj, Gandhinagar 382355, Gujarat, India.
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Alketbi L, Al-Ali A, Talaat IM, Hamid Q, Bajbouj K. The Role of ATP-Binding Cassette Subfamily A in Colorectal Cancer Progression and Resistance. Int J Mol Sci 2023; 24:1344. [PMID: 36674859 PMCID: PMC9860967 DOI: 10.3390/ijms24021344] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 12/29/2022] [Accepted: 01/06/2023] [Indexed: 01/12/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. CRC arises due to mutations that can affect oncogenes, tumour suppressor genes and DNA repair genes. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are some of the major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, ABC transporters have additional roles in cancer development beyond multidrug resistance. In CRC, lipid dysregulation has a key role in tumour development and progression, as cancer cells rely on lipids for energy and rapid cell proliferation. ABC subfamily A (ABCA) contains the largest members of ABC proteins, mainly known for their role in lipid transport, mostly membrane lipids such as cholesterol and phospholipids. Although the exact mechanism of action of these members is not confirmed, their expression is usually correlated with tumour progression and therapy resistance, probably due to their role in lipid homeostasis. CRC shows alteration in the expression of ABCA transporters, which is usually linked to poor prognosis and overall survival. Therefore, as lipid transporters, their role in CRC is investigated, and their diagnostic and prognostic potential is evaluated. This minireview presents evidence from various studies suggesting that ABCA transporters might have an active role in CRC and can be utilized as potential diagnostic and therapeutic targets.
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Affiliation(s)
- Latifa Alketbi
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
| | - Abeer Al-Ali
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
| | - Iman M. Talaat
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Faculty of Medicine, Alexandria University, Alexandria 21544, Egypt
| | - Qutayba Hamid
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Meakins-Christie Laboratories, McGill University, Montreal, QC H3A 0G4, Canada
| | - Khuloud Bajbouj
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
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Zhang Q, Fang H, Zhu Z. NRBP1 modulates uric acid transporter ABCG2 expression by activating the Wnt/β-catenin pathway in HK-2 cells. Nefrologia 2022:S2013-2514(22)00140-7. [PMID: 36437206 DOI: 10.1016/j.nefroe.2022.11.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 09/04/2021] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND Nuclear receptor binding protein 1 (NRBP1) and ATP-binding cassette subfamily G member 2 (ABCG2) was the gout risk gene and high-capacity urate exporter respectively. However, the relationship between NRBP1 and ABCG2 and the underlying molecular mechanism contributing to these associations are unknown. METHODS Firstly, the efficiency of the overexpression and knockdown of NRBP1 was confirmed by western blot. Next, the effect of NRBP1 overexpression and knockdown on the expression of ABCG2, organic anion transporter 1 (OAT1), glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) was detected by qRT-PCR and western blot. At the same time, the cellular location of ABCG2 and its expression after NRBP1 overexpression and knockdown was tested by immunofluorescence (IF) staining. Then, the mechanism of NRBP1 modulates ABCG2 expression was evaluated by western blot with or without the β-catenin inhibitor (21H7). RESULTS The lentivirus system was used to generate stable NRBP1 overexpression, while the plasmids carrying a NRBP1 siRNA was generated to knockdown NRBP1 expression in HK-2 cells. Meanwhile, the overexpression of NRBP1 significantly decreased the mRNAs and proteins expression of GLUT9 and URAT1, while the knockdown of NRBP1 increased the mRNAs and proteins expression of ABCG2 significantly. In addition, the NRBP1 modulates the expression of ABCG2 was by ctivating the Wnt/β-catenin pathway in HK-2 cells according to the IF and western blot results. CONCLUSION Taken together, our study demonstrated that NRBP1 inhibition played an essential role in attenuating hyperuricemia and gout by upregulation of ABCG2 via Wnt/β-catenin signaling pathway in HK-2 cells.
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Affiliation(s)
- Qiankun Zhang
- Division of Nephrology, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui 323000, China
| | - Hang Fang
- Division of Nephrology, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui 323000, China; Institute of Nephrology, Zhejiang University, Hangzhou 310003, China
| | - Zaihua Zhu
- Division of Rheumatology and Immunology, Huashan Hospital Fudan University, Shanghai 200000, China.
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Doneti R, Pasha A, Botlagunta M, Heena SK, Mutyala VVVP, Pawar SC. Molecular docking, synthesis, and biological evaluation of 7-azaindole-derivative (7AID) as novel anti-cancer agent and potent DDX3 inhibitor:-an in silico and in vitro approach. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:179. [PMID: 36048256 DOI: 10.1007/s12032-022-01826-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022]
Abstract
The DEAD-box helicase family member DDX3 is involved in many diseases, such as viral infection, inflammation, and cancer. Many studies in the last decade have revealed the role of DDX3 in tumorigenesis and metastasis. DDX3 has both tumour suppressor and oncogenic effect, in the present study we have evaluated the expression levels of DDX3 in cervical squamous cell carcinoma at mRNA level via real-time PCR and protein level via Immunohistochemistry. DDX3 has become a molecule of interest in cancer biology that promotes drug resistance by adaptive response inevitably leading to treatment failure. One approach to avoid the development of resistant to disease is to create novel drugs that target the overexpressed proteins, we designed and synthesized a novel 7-azaindole derivative (7-AID) compound, {5-[1H-pyrrolo (2, 3-b) pyridin-5-yl] pyridin-2-ol]} that could lodge within the adenosine-binding pocket of the DDX3 (PDB ID: 2I4I). The binding efficacy of 7-AID compound with DDX3 was analysed by molecular docking studies. 7-AID was found to interact with the key residues Tyr200 and Arg202 from the Q-motif rendered by π-interactions and hydrogen bonds within the binding pocket with good docking score - 7.99 kcal/mol. The cytotoxicity effect of 7-AID compound was evaluated using MTT assay on human cervical carcinoma cells (HeLa) and breast cancer cells (MCF-7 and MDA MB-231) and the compound shown effective inhibitory concentration (IC50) on Hela cells 16.96 µM/ml and 14.12 and 12.69 µM/ml on MCF-7 and MDA MB-231, respectively. Further, the in-vitro, in-vivo anti-cancer and anti-angiogenic assessment of 7-AID compound was evaluated on Hela cells using scratch wound-healing assay, DAPI staining, cell cycle analysis, immunoblotting, and chorioallontoic membrane assay. Furthermore, the inhibitory effect of derivative compound on DDX3 was investigated in HeLa, MCF-7, and MDA MB-231 cells at the mRNA and protein levels. The results showed that the 7-AID compound effectively inhibited DDX3 in a dose-dependent manner, and the findings suggest that the compound could be used as a potential DDX3 inhibitor.
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Affiliation(s)
- Ravinder Doneti
- Department of Genetics & Biotechnology, Osmania University, Hyderabad, Telangana, 500 007, India
| | - Akbar Pasha
- Department of Genetics & Biotechnology, Osmania University, Hyderabad, Telangana, 500 007, India
| | - Mahendran Botlagunta
- School of Biosciences Engineering and Technology, VIT Bhopal University, Bhopal, Madhya Pradesh, 466114, India
| | - S K Heena
- Department of Pathology, Osmania Medical College, Hyderabad, Telangana, 500095, India
| | | | - Smita C Pawar
- Department of Genetics & Biotechnology, Osmania University, Hyderabad, Telangana, 500 007, India.
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Kast RE, Alfieri A, Assi HI, Burns TC, Elyamany AM, Gonzalez-Cao M, Karpel-Massler G, Marosi C, Salacz ME, Sardi I, Van Vlierberghe P, Zaghloul MS, Halatsch ME. MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen. Cancers (Basel) 2022; 14:2563. [PMID: 35626167 PMCID: PMC9140192 DOI: 10.3390/cancers14102563] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/11/2022] [Accepted: 05/17/2022] [Indexed: 12/12/2022] Open
Abstract
In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells' growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass-by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs-celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan-to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of-not a replacement for-previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs.
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Affiliation(s)
| | - Alex Alfieri
- Department of Neurosurgery, Cantonal Hospital of Winterthur, 8400 Winterthur, Switzerland; (A.A.); (M.-E.H.)
| | - Hazem I. Assi
- Naef K. Basile Cancer Center, American University of Beirut, Beirut 1100, Lebanon;
| | - Terry C. Burns
- Department of Neurological Surgery, Mayo Clinic, Rochester, MN 55905, USA;
| | - Ashraf M. Elyamany
- Oncology Unit, Hemato-Oncology Department, SECI Assiut University Egypt/King Saud Medical City, Riyadh 7790, Saudi Arabia;
| | - Maria Gonzalez-Cao
- Translational Cancer Research Unit, Dexeus University Hospital, 08028 Barcelona, Spain;
| | | | - Christine Marosi
- Clinical Division of Medical Oncology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria;
| | - Michael E. Salacz
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA;
| | - Iacopo Sardi
- Department of Pediatric Oncology, Meyer Children’s Hospital, Viale Pieraccini 24, 50139 Florence, Italy;
| | - Pieter Van Vlierberghe
- Department of Biomolecular Medicine, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium;
| | - Mohamed S. Zaghloul
- Children’s Cancer Hospital & National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Marc-Eric Halatsch
- Department of Neurosurgery, Cantonal Hospital of Winterthur, 8400 Winterthur, Switzerland; (A.A.); (M.-E.H.)
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NRBP1 modulates uric acid transporter ABCG2 expression by activating the Wnt/β-catenin pathway in HK-2 cells. Nefrologia 2021. [DOI: 10.1016/j.nefro.2021.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Gholamian Dehkordi N, Mirzaei SA, Elahian F. Pharmacodynamic mechanisms of anti-inflammatory drugs on the chemosensitization of multidrug-resistant cancers and the pharmacogenetics effectiveness. Inflammopharmacology 2020; 29:49-74. [PMID: 33070257 DOI: 10.1007/s10787-020-00765-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 09/27/2020] [Indexed: 01/07/2023]
Abstract
Drug resistance as a remarkable issue in cancer treatment is associated with inflammation which occurs through complex chemical reactions in the tumor microenvironment. Recent studies have implicated that glucocorticoids and NSAIDs are mainly useful combinations for inflammatory response modulation in chemotherapeutic protocols for cancer treatment. Immunosuppressive actions of glucocorticoids and NSAIDs are mainly mediated by the transrepression or activation regulation of inflammatory genes with different DNA-bound transcription factors including AP-1, NFAT, NF-κB, STAT and also, varying functions of COX enzymes in cancer cells. Interestingly, many investigations have proved the benefits of these anti-inflammatory agents in the quenching of multidrug resistance pathways. Numerous analyses on the ABC transporter promoters showed conserved nucleotide sequences with several DNA response elements that participate in transcriptional regulation. Furthermore, genetic variations in nucleotide sequences of membrane transporters were strongly associated with changes in these transporters' expression or function and a substantial impact on systemic drug exposure and toxicity. It appeared that several polymorphisms in MDR transporter genes especially MDR1 have influenced the regulatory mechanisms and explained differences in glucocorticoid responses.
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Affiliation(s)
- Neda Gholamian Dehkordi
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Seyed Abbas Mirzaei
- Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Fatemeh Elahian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
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Kadioglu O, Saeed MEM, Munder M, Spuller A, Greten HJ, Efferth T. Effect of ABC transporter expression and mutational status on survival rates of cancer patients. Biomed Pharmacother 2020; 131:110718. [PMID: 32932043 DOI: 10.1016/j.biopha.2020.110718] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 08/28/2020] [Accepted: 08/30/2020] [Indexed: 02/07/2023] Open
Abstract
ATP-binding cassette (ABC) transporters mediate multidrug resistance in cancer. In contrast to DNA single nucleotide polymorphisms in normal tissues, the role of mutations in tumors is unknown. Furthermore, the significance of their expression for prediction of chemoresistance and survival prognosis is still under debate. We investigated 18 tumors by RNA-sequencing. The mutation rate varied from 27,507 to 300885. In ABCB1, three hotspots with novel mutations were in transmembrane domains 3, 8, and 9. We also mined the cBioPortal database with 11,814 patients from 23 different tumor entities. We performed Kaplan-Meier survival analyses to investigate the effect of ABC transporter expression on survival rates of cancer patients. Novel mutations were also found in ABCA2, ABCA3, ABCB2, ABCB5, ABCC1-6, and ABCG2. Mining the cBioPortal database with 11,814 patients from 23 different tumor entities validated our results. Missense and in-frame mutations led to altered binding of anticancer drugs in molecular docking approaches. The ABCB1 nonsense mutation Q856* led to a truncated P-glycoprotein, which may sensitize tumors to anticancer drugs. The search for ABC transporter nonsense mutations represents a novel approach for precision medicine.. Low ABCB1 mRNA expression correlated with significantly longer survival in ovarian or kidney cancer and thymoma. In cancers of breast, kidney or lung, ABC transporter expression correlated with different tumor stages and human populations as further parameters to refine strategies for more individualized chemotherapy.
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Affiliation(s)
- Onat Kadioglu
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Mohamed E M Saeed
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Markus Munder
- Department of Medicine (Hematology, Oncology, and Pneumology), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | | | - Henry Johannes Greten
- Abel Salazar Biomedical Sciences Institute, University of Porto, Portugal; Heidelberg School of Chinese Medicine, Heidelberg, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
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Kopecka J, Trouillas P, Gašparović AČ, Gazzano E, Assaraf YG, Riganti C. Phospholipids and cholesterol: Inducers of cancer multidrug resistance and therapeutic targets. Drug Resist Updat 2020; 49:100670. [DOI: 10.1016/j.drup.2019.100670] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/14/2019] [Accepted: 11/17/2019] [Indexed: 12/13/2022]
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12
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Identification of Novel Rare ABCC1 Transporter Mutations in Tumor Biopsies of Cancer Patients. Cells 2020; 9:cells9020299. [PMID: 31991926 PMCID: PMC7072590 DOI: 10.3390/cells9020299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/22/2020] [Accepted: 01/23/2020] [Indexed: 11/17/2022] Open
Abstract
The efficiency of chemotherapy drugs can be affected by ATP-binding cassette (ABC) transporter expression or by their mutation status. Multidrug resistance is linked with ABC transporter overexpression. In the present study, we performed rare mutation analyses for 12 ABC transporters related to drug resistance (ABCA2, -A3, -B1, -B2, -B5, -C1, -C2, -C3, -C4, -C5, -C6, -G2) in a dataset of 18 cancer patients. We focused on rare mutations resembling tumor heterogeneity of ABC transporters in small tumor subpopulations. Novel rare mutations were found in ABCC1, but not in the other ABC transporters investigated. Diverse ABCC1 mutations were found, including nonsense mutations causing premature stop codons, and compared with the wild-type protein in terms of their protein structure. Nonsense mutations lead to truncated protein structures. Molecular docking and heat map analyses of ABCC1/MRP1 pointed out that Lys498* appeared in a separate cluster branch due to the large deletion, leading to a massive disruption in the protein conformation. The resulting proteins, which are nonfunctional due to nonsense mutations in tumors, offer a promising chemotherapy strategy since tumors with nonsense mutations may be more sensitive to anticancer drugs than wild-type ABCC1-expressing tumors. This could provide a novel tumor-specific toxicity strategy and a way to overcome drug resistance.
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Yang J, Yin Z, Li Y, Liu Y, Huang G, Gu C, Fei J. The Identification of Long Non-coding RNA H19 Target and Its Function in Chronic Myeloid Leukemia. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 19:1368-1378. [PMID: 32160707 PMCID: PMC7044501 DOI: 10.1016/j.omtn.2020.01.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 12/29/2019] [Accepted: 01/14/2020] [Indexed: 12/19/2022]
Abstract
H19 is a long non-coding RNA which was lowly expressed in chronic myeloid leukemia (CML). Here, we found that the overexpression of H19 significantly inhibited cell viability and colony formation and prolongs survival in CML cell lines and three xenografted mouse models. The H19 target proteins and microRNAs (miRNAs) were identified using a combination of computational prediction and RNA pull-down, including PCBP1, FUS protein, and miR-19a-3p and miR-106b-5p. Targeting PCBP1, FUS protein, miR-19a-3p, and miR-106b-5p significantly inhibits the cell growth and colony formation of CML cell lines. Co-overexpression of H19 and PCBP1, FUS, miR-19a-3p, and miR-106b-5p decreases the inhibitory effect of H19 in CML. These findings might provide a novel molecular insight into CML.
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Affiliation(s)
- Juhua Yang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China; Engineering Technology Research Center of Drug Development for Small Nucleic Acid, Guangdong Province, China; Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou, China
| | - Zhao Yin
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China; Engineering Technology Research Center of Drug Development for Small Nucleic Acid, Guangdong Province, China; Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou, China; Insititute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China
| | - Yumin Li
- Medical Laboratory of Shenzhen Luohu People's Hospital, Shenzhen, China
| | - Yanjun Liu
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China; Engineering Technology Research Center of Drug Development for Small Nucleic Acid, Guangdong Province, China; Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou, China
| | - Guiping Huang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China; Engineering Technology Research Center of Drug Development for Small Nucleic Acid, Guangdong Province, China; Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou, China
| | - Chunming Gu
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China; Engineering Technology Research Center of Drug Development for Small Nucleic Acid, Guangdong Province, China; Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou, China; Insititute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China
| | - Jia Fei
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China; Engineering Technology Research Center of Drug Development for Small Nucleic Acid, Guangdong Province, China; Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou, China; Insititute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China.
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14
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Hartz AMS, Rempe RG, Soldner ELB, Pekcec A, Schlichtiger J, Kryscio R, Bauer B. Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy. FASEB J 2019; 33:14281-14295. [PMID: 31661303 DOI: 10.1096/fj.201901369rr] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Blood-brain barrier dysfunction in epilepsy contributes to seizures and resistance to antiseizure drugs. Reports show that seizures increase brain glutamate levels, leading to barrier dysfunction. One component of barrier dysfunction is overexpression of the drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Based on our previous studies, we hypothesized that glutamate released during seizures activates cytosolic phospholipase A2 (cPLA2), resulting in P-gp and BCRP overexpression. We exposed isolated rat brain capillaries to glutamate ex vivo and used an in vivo-ex vivo approach of isolating brain capillaries from rats after status epilepticus (SE) and in chronic epileptic (CE) rats. Glutamate increased cPLA2, P-gp, and BCRP protein and activity levels in isolated brain capillaries. We confirmed the role of cPLA2 in the signaling pathway in brain capillaries from male and female mice lacking cPLA2. We also demonstrated, in vivo, that cPLA2 inhibition prevents overexpression of P-gp and BCRP at the blood-brain barrier in rats after status epilepticus and in CE rats. Our data support the hypothesis that glutamate signals cPLA2 activation, resulting in overexpression of blood-brain barrier P-gp and BCRP.-Hartz, A. M. S., Rempe, R. G., Soldner, E. L. B., Pekcec, A., Schlichtiger, J., Kryscio, R., Bauer, B. Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy.
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Affiliation(s)
- Anika M S Hartz
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.,Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
| | - Ralf G Rempe
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA
| | - Emma L B Soldner
- Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota, USA
| | - Anton Pekcec
- Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota, USA
| | - Juli Schlichtiger
- Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota, USA
| | - Richard Kryscio
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.,Department of Statistics, University of Kentucky, Lexington, Kentucky, USA
| | - Bjoern Bauer
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA.,Epilepsy Center, University of Kentucky, Lexington, Kentucky, USA
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15
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Pasello M, Giudice AM, Scotlandi K. The ABC subfamily A transporters: Multifaceted players with incipient potentialities in cancer. Semin Cancer Biol 2019; 60:57-71. [PMID: 31605751 DOI: 10.1016/j.semcancer.2019.10.004] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 09/30/2019] [Accepted: 10/04/2019] [Indexed: 12/12/2022]
Abstract
Overexpression of ATP-binding cassette (ABC) transporters is a cause of drug resistance in a plethora of tumors. More recent evidence indicates additional contribution of these transporters to other processes, such as tumor cell dissemination and metastasis, thereby extending their possible roles in tumor progression. While the role of some ABC transporters, such as ABCB1, ABCC1 and ABCG2, in multidrug resistance is well documented, the mechanisms by which ABC transporters affect the proliferation, differentiation, migration and invasion of cancer cells are still poorly defined and are frequently controversial. This review, summarizes recent advances that highlight the role of subfamily A members in cancer. Emerging evidence highlights the potential value of ABCA members as biomarkers of risk and response in different tumors, but information is disperse and very little is known about their possible mechanisms of action. The only clear evidence is that ABCA members are involved in lipid metabolism and homeostasis. In particular, the relationship between ABCA1 and cholesterol is becoming evident in different fields of biology, including cancer. In parallel, emerging findings indicate that cholesterol, the main component of cell membranes, can influence many physiological and pathological processes, including cell migration, cancer progression and metastasis. This review aims to link the dispersed knowledge regarding the relationship of ABCA members with lipid metabolism and cancer in an effort to stimulate and guide readers to areas that the writers consider to have significant impact and relevant potentialities.
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Affiliation(s)
- Michela Pasello
- CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Bologna, 40136, Italy.
| | - Anna Maria Giudice
- CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Bologna, 40136, Italy; Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, 40126, Italy
| | - Katia Scotlandi
- CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Bologna, 40136, Italy.
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16
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Design of colloidal drug carriers of celecoxib for use in treatment of breast cancer and leukemia. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 103:109874. [DOI: 10.1016/j.msec.2019.109874] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 03/23/2019] [Accepted: 06/07/2019] [Indexed: 12/30/2022]
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17
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Doxorubicin as a fluorescent reporter identifies novel MRP1 (ABCC1) inhibitors missed by calcein-based high content screening of anticancer agents. Biomed Pharmacother 2019; 118:109289. [PMID: 31401398 DOI: 10.1016/j.biopha.2019.109289] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 07/28/2019] [Accepted: 07/30/2019] [Indexed: 01/30/2023] Open
Abstract
Multidrug resistance protein 1 (MRP1/ABCC1) actively transports a variety of drugs, toxic molecules and important physiological substrates across the plasma membrane. It can confer broad-spectrum multidrug resistance and can decrease the bioavailability of many important drugs. Substrates of MRP1 include anti-cancer agents, antibiotics, antivirals, antidepressants and anti-inflammatory drugs. Using calcein as a fluorescent reporter in a high content uptake assay, we recently reported the identification of 12 MRP1 inhibitors after screening an anti-cancer library of 386 compounds. Here, we describe the development of a new high content imaging-based uptake assay using doxorubicin as a fluorescent reporter. Screening the same anti-cancer library of 386 compounds, the new assay identified a total of 28 MRP1 inhibitors including 16 inhibitors that have not been previously reported as inhibitors of MRP1. Inhibition of MRP1 activity was confirmed using flow cytometry and confocal microscopy-based transport assays. Six drugs (afatinib, celecoxib, doramapimod, mifepristone, MK-2206 and rosiglitazone) were evaluated for their ability to reverse resistance of MRP1-overexpressing H69AR lung cancer cells against vincristine, doxorubicin and etoposide. Mifepristone and doramapimod were most effective in reversal of resistance against vincristine while mifepristone and rosiglitazone were most successful in resensitizing H69AR cells against doxorubicin. Furthermore, resistance towards etoposide was completely reversed in the presence of celecoxib or doramapimod. Selected drugs were also evaluated for resistance reversal in HEK cells that overexpress P-glycoprotein or breast cancer resistance protein. Our results indicate mifepristone and doramapimod as pan inhibitors of these three drug transporters while celecoxib exhibited selective MRP1 inhibition. Together, our findings signify the importance of MRP1 in drug discovery and demonstrate the effectiveness and value of doxorubicin-based high content screening approach. Anti-cancer agents that exhibit MRP1 inhibition may be used to reverse multidrug resistance or to improve the efficacy and reduce the toxicity of various cancer chemotherapies. On the other hand, anti-cancer drugs that did not interact with MRP1 carry a low risk for developing MRP1-mediated resistance.
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18
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Moon HJ, Park SY, Lee SH, Kang CD, Kim SH. Nonsteroidal Anti-inflammatory Drugs Sensitize CD44-Overexpressing Cancer Cells to Hsp90 Inhibitor Through Autophagy Activation. Oncol Res 2019; 27:835-847. [PMID: 30982499 PMCID: PMC7848457 DOI: 10.3727/096504019x15517850319579] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Recently, novel therapeutic strategies have been designed with the aim of killing cancer stem-like cells (CSCs), and considerable interest has been generated in the development of specific therapies that target stemness-related marker of CSCs. In this study, nonsteroidal anti-inflammatory drugs (NSAIDs) significantly potentiated Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-mediated cytotoxicity through apoptotic and autophagic cell death induction, but COX-2-inhibitory function was not required for NSAID-induced autophagy in CD44-overexpressing human chronic myeloid leukemia K562 (CD44highK562) cells. Importantly, we found that treatment with NSAIDs resulted in a dose-dependent increase in LC3-II level and decrease in p62 level and simultaneous reduction in multiple stemness-related markers including CD44, Oct4, c-Myc, and mutant p53 (mutp53) in CD44highK562 cells, suggesting that NSAIDs could induce autophagy, which might mediate degradation of stemness-related marker proteins. Activation of AMPK and inhibition of Akt/mTOR/p70S6K/4EBP1 participated in NSAID-induced autophagy in CD44highK562 cells. In addition, treatment of CD44highK562 cells with NSAIDs inhibited expression of HSF1/Hsps, which resulted in suppression of 17-AAG-induced activation of Hsp70, leading to reversal of 17-AAG resistance and sensitization of CD44highK562 cells to 17-AAG by NSAIDs. In conclusion, combining NSAIDs with Hsp90 inhibitor may offer one of the most promising strategies for eradication of CD44-overexpressing CSCs.
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Affiliation(s)
- Hyun-Jung Moon
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea
| | - So-Young Park
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea
| | - Su-Hoon Lee
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea
| | - Chi-Dug Kang
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea
| | - Sun-Hee Kim
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea
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19
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Zhou G, Latchoumanin O, Hebbard L, Duan W, Liddle C, George J, Qiao L. Aptamers as targeting ligands and therapeutic molecules for overcoming drug resistance in cancers. Adv Drug Deliv Rev 2018. [DOI: '10.1016/j.addr.2018.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2023]
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20
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Zhou G, Latchoumanin O, Hebbard L, Duan W, Liddle C, George J, Qiao L. Aptamers as targeting ligands and therapeutic molecules for overcoming drug resistance in cancers. Adv Drug Deliv Rev 2018; 134:107-121. [PMID: 29627370 DOI: 10.1016/j.addr.2018.04.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 03/28/2018] [Accepted: 04/03/2018] [Indexed: 12/18/2022]
Abstract
Traditional anticancer therapies are often unable to completely eradicate the tumor bulk due to multi-drug resistance (MDR) of cancers. A number of mechanisms such as micro-environmental stress and overexpression of drug efflux pumps are involved in the MDR process. Hence, therapeutic strategies for overcoming MDR are urgently needed to improve cancer treatment efficacy. Aptamers are short single-stranded oligonucleotides or peptides exhibiting unique three-dimensional structures and possess several unique advantages over conventional antibodies such as low immunogenicity and stronger tissue-penetration capacity. Aptamers targeting cancer-associated receptors have been explored to selectively deliver a therapeutic cargo (anticancer drugs, siRNAs, miRNAs and drug-carriers) to the intratumoral compartment where they can exert better tumor-killing effects. In this review, we summarize current knowledge of the multiple regulatory mechanisms of MDR, with a particular emphasis on aptamer-mediated novel therapeutic agents and strategies that seek to reversing MDR. The challenges associated with aptamer-based agents and approaches are also discussed.
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Affiliation(s)
- Gang Zhou
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia
| | - Olivier Latchoumanin
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia
| | - Lionel Hebbard
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia
| | - Wei Duan
- School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Victoria 3217, Australia
| | - Christopher Liddle
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia.
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW 2145, Australia.
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21
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microRNA-199a/b-5p enhance imatinib efficacy via repressing WNT2 signaling-mediated protective autophagy in imatinib-resistant chronic myeloid leukemia cells. Chem Biol Interact 2018; 291:144-151. [PMID: 29890129 DOI: 10.1016/j.cbi.2018.06.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 05/18/2018] [Accepted: 06/06/2018] [Indexed: 01/22/2023]
Abstract
Imatinib (IM) is a first-line therapeutic drug for chronic myeloid leukemia (CML), a hematological disease. Mutations in the BCR-ABL domain increase formation of IM resistance in CML. However, not all patients are BCR-ABL domain-mutant dependent. Investigating non-mutant mechanisms in the development of acquired IM resistance is a critical issue. We explored the mechanisms which influence IM efficacy and resistance in CML. Higher protective autophagy was identified in IM-resistant K562 (K562R) cells. Inhibition of autophagy by the inhibitors, chloroquine and 3-methyladenine, enhanced IM's efficacy in K562R cells. In addition, microRNA (miR)-199a/b-5p were downregulated in K562R cells compared to parent cells. Overexpression of miR-199a/b-5p reduced autophagy and induced cell apoptosis, resulting in enhanced IM's efficacy in K562R cells. Moreover, expression levels of the Wingless-type MMTV integration site family member 2 (WNT2), a positive regulator of autophagy, were significantly higher in K562R cells, and it was validated as a direct target gene of miR-199a/b-5p. Overexpressions of miR-199a/b-5p inhibited WNT2 downstream signaling. Furthermore, overexpression and knockdown of WNT2 influenced autophagy formation and CML drug sensitivity to IM. Overexpression of WNT2 could also reverse miR-199a/b-5p-enhanced IM efficacy in K562R cells. These results emphasized that miR-199a/b-5p inhibited autophagy via repressing WNT2 signaling and might provide novel therapeutic strategies for future IM-resistant CML therapy and drug development.
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Stefan SM, Wiese M. Small-molecule inhibitors of multidrug resistance-associated protein 1 and related processes: A historic approach and recent advances. Med Res Rev 2018; 39:176-264. [DOI: 10.1002/med.21510] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/05/2018] [Accepted: 04/28/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Sven Marcel Stefan
- Pharmaceutical Institute; Rheinische Friedrich-Wilhelms-University; Bonn Germany
| | - Michael Wiese
- Pharmaceutical Institute; Rheinische Friedrich-Wilhelms-University; Bonn Germany
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23
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Bryukhovetskiy I, Ponomarenko A, Lyakhova I, Zaitsev S, Zayats Y, Korneyko M, Eliseikina M, Mischenko P, Shevchenko V, Shanker Sharma H, Sharma A, Khotimchenko Y. Personalized regulation of glioblastoma cancer stem cells based on biomedical technologies: From theory to experiment (Review). Int J Mol Med 2018; 42:691-702. [PMID: 29749540 PMCID: PMC6034919 DOI: 10.3892/ijmm.2018.3668] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 05/02/2018] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors. GBM represents >50% of primary tumors of the nervous system and ~20% of intracranial neoplasms. Standard treatment involves surgery, radiation and chemotherapy. However, the prognosis of GBM is usually poor, with a median survival of 15 months. Resistance of GBM to treatment can be explained by the presence of cancer stem cells (CSCs) among the GBM cell population. At present, there are no effective therapeutic strategies for the elimination of CSCs. The present review examined the nature of human GBM therapeutic resistance and attempted to systematize and put forward novel approaches for a personalized therapy of GBM that not only destroys tumor tissue, but also regulates cellular signaling and the morphogenetic properties of CSCs. The CSCs are considered to be an informationally accessible living system, and the CSC proteome should be used as a target for therapy directed at suppressing clonal selection mechanisms and CSC generation, destroying CSC hierarchy, and disrupting the interaction of CSCs with their microenvironment and extracellular matrix. These objectives can be achieved through the use of biomedical cellular products.
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Affiliation(s)
| | | | - Irina Lyakhova
- Far Eastern Federal University, Vladivostok 690091, Russia
| | - Sergey Zaitsev
- Far Eastern Federal University, Vladivostok 690091, Russia
| | - Yulia Zayats
- Far Eastern Federal University, Vladivostok 690091, Russia
| | - Maria Korneyko
- Far Eastern Federal University, Vladivostok 690091, Russia
| | - Marina Eliseikina
- National Scientific Center of Marine Biology of Far Eastern Branch of The Russian Academy of Sciences, Vladivostok 690059, Russia
| | | | | | - Hari Shanker Sharma
- International Experimental CNS Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, University Hospital, Uppsala University, Uppsala SE‑75185, Sweden
| | - Aruna Sharma
- International Experimental CNS Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, University Hospital, Uppsala University, Uppsala SE‑75185, Sweden
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Gao J, Mfuh A, Amako Y, Woo CM. Small Molecule Interactome Mapping by Photoaffinity Labeling Reveals Binding Site Hotspots for the NSAIDs. J Am Chem Soc 2018. [PMID: 29543447 DOI: 10.1021/jacs.7b11639] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Jinxu Gao
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, Massachusetts 02138, United States
| | - Adelphe Mfuh
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, Massachusetts 02138, United States
| | - Yuka Amako
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, Massachusetts 02138, United States
| | - Christina M. Woo
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, Massachusetts 02138, United States
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25
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Moon HJ, Kim HB, Lee SH, Jeun SE, Kang CD, Kim SH. Sensitization of multidrug-resistant cancer cells to Hsp90 inhibitors by NSAIDs-induced apoptotic and autophagic cell death. Oncotarget 2018. [PMID: 29541415 PMCID: PMC5834263 DOI: 10.18632/oncotarget.24130] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
NSAIDs (non-steroidal anti-inflammatory drugs) have potential use as anticancer agents, either alone or in combination with other cancer therapies. We found that NSAIDs including celecoxib (CCB) and ibuprofen (IBU) significantly potentiated the cytotoxicity of Hsp90 inhibitors in human multidrug-resistant (MDR) cells expressing high levels of mutant p53 (mutp53) protein and P-glycoprotein (P-gp), and reversed Hsp90 inhibitor resistance caused by activation of heat shock factor 1 (HSF1) and by up-regulation of heat shock proteins (Hsps) and P-gp. Inhibition of Akt/mTOR and STAT3 pathways by CCB induced autophagy, which promoted the degradation of mutp53, one of Hsp90 client proteins, and subsequently down-regulated HSF1/Hsps and P-gp. Inhibition of autophagy prevented mutp53 degradation and CCB-induced apoptosis, and inhibition of caspase-3-mediated apoptotic pathway by Z-DEVD-FMK did not completely block CCB-induced cell death in MDR cells, suggesting that autophagic and apoptotic cell death may contribute to CCB-induced cytotoxicity in MDR cells. Furthermore, CCB and IBU suppressed Hsp90 inhibitor-induced HSF1/Hsp70/P-gp activity and mutp53 expression in MDR cells. Our results suggest that NSAIDs can be used as potential Hsp90 inhibitor chemosensitizers and reverse resistance of MDR cells to Hsp90 inhibitors via induction of apoptosis and autophagy. These results might enable the use of lower, less toxic doses of Hsp90 inhibitors and facilitate the design of practically applicable, novel combination therapy for the treatment of MDR cancer.
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Affiliation(s)
- Hyun-Jung Moon
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea
| | - Hak-Bong Kim
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea
| | - Su-Hoon Lee
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea
| | - So-Eun Jeun
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea
| | - Chi-Dug Kang
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea
| | - Sun-Hee Kim
- Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea
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26
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Zhu H, Gao J, Wang L, Qian KJ, Cai LP. In vitro study on reversal of ovarian cancer cell resistance to cisplatin by naringin via the nuclear factor-κB signaling pathway. Exp Ther Med 2018; 15:2643-2648. [PMID: 29456667 DOI: 10.3892/etm.2018.5695] [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] [Received: 10/27/2016] [Accepted: 04/11/2017] [Indexed: 12/29/2022] Open
Abstract
The aim of the present study was to investigate the mechanism of action by which naringin reverses the resistance of ovarian cancer cells to cisplatin. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and western blotting assays were used to detect the effects of different concentrations of naringin on the expressions of nuclear factor (NF)-κB and P-glycoprotein (P-gp) in the SKOV3/CDDP cell line. Small interfering RNA (siRNA) targeting NF-κB was designed and synthesized to silence NF-κB, and recombinant plasmid vectors overexpressing NF-κB were constructed to transfect cells. RT-qPCR and western blotting assays were subsequently performed to detect the effects of NF-κB on the expression of P-gp at the mRNA and protein levels. Naringin was added to the NF-κB-overexpressing SKOV3/CDDP cells and cultured for 48 h, followed by the detection of the expression of P-gp. RT-PCR and western blotting results demonstrated that the gene and protein expressions of NF-κB and P-gp were significantly decreased in a dose-dependent manner by naringin treatment (P<0.05). In cells overexpressing NF-κB, P-gp expression was significantly elevated (P<0.05), and the expression of P-gp was significantly decreased when NF-κB was silenced (P<0.05). Treatment with naringin was able to significantly ameliorate the NF-κB-induced overexpression of P-gp (P<0.05). These results indicate that naringin is able to inhibit the expression of NF-κB and P-gp in SKOV3/CDDP cells. Such an inhibitory effect may increase gradually with concentration, and is associated with blockade of the NF-κB signaling pathway. This pathway may represent one of the mechanisms of action by which Naringin reverses resistance to platinum-based agents in ovarian cancer cells.
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Affiliation(s)
- Hong Zhu
- Department of Clinical Medicine, Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jun Gao
- Department of Gynecology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Lei Wang
- Department of Gynecology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ke-Jian Qian
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Li-Ping Cai
- Department of Gynecology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Wnt Signaling in Hematological Malignancies. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 153:321-341. [PMID: 29389522 DOI: 10.1016/bs.pmbts.2017.11.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Leukemia and lymphoma are a wide encompassing term for a diverse set of blood malignancies that affect people of all ages and result in approximately 23,000 deaths in the United States per year (Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.). Hematopoietic stem cells (HSCs) are tissue-specific stem cells at the apex of the hierarchy that gives rise to all of the terminally differentiated blood cells, through progressively restricted progenitor populations, a process that is known to be Wnt-responsive. In particular, the progenitor populations are subject to uncontrolled expansion during oncogenic processes, namely the common myeloid progenitor and common lymphoid progenitor, as well as the myeloblast and lymphoblast. Unregulated growth of these cell-types leads to mainly three types of blood cancers (i.e., leukemia, lymphoma, and myeloma), which frequently exhibit deregulation of the Wnt signaling pathway. Generally, leukemia is caused by the expansion of myeloid progenitors, leading to an overproduction of white blood cells; as such, patients are unable to make sufficient numbers of red blood cells and platelets. Likewise, an overproduction of lymphocytes leads to clogging of the lymph system and impairment of the immune system in lymphomas. Finally, cancer of the plasma cells in the blood is called myeloma, which also leads to immune system failure. Within each of these three types of blood cancers, there are multiple subtypes, usually characterized by their timeline of onset and their cell type of origin. Of these, 85% of leukemias are encompassed by the four most common diseases, that is, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL); AML accounts for the majority of leukemia-related deaths (Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.). Through understanding how HSCs are normally developed and maintained, we can understand how the normal functions of these pathways are disrupted during blood cancer progression; the Wnt pathway is important in regulation of both normal and malignant hematopoiesis. In this chapter, we will discuss the role of Wnt signaling in normal and aberrant hematopoiesis. Our understanding the relationship between Wnt and HSCs will provide novel insights into therapeutic targets.
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Davis W, Tew KD. ATP-binding cassette transporter-2 (ABCA2) as a therapeutic target. Biochem Pharmacol 2017; 151:188-200. [PMID: 29223352 DOI: 10.1016/j.bcp.2017.11.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 11/27/2017] [Indexed: 12/28/2022]
Abstract
The ATP binding cassette transporter ABCA2 is primarily an endolysosomal membrane protein that demonstrates pleiotropic functionalities, coalescing around the maintenance of homeostasis of sterols, sphingolipids and cholesterol. It is most highly expressed in brain tissue and ABCA2 knockout mice express neurological defects consistent with aberrant myelination. Increased expression of the transporter has been linked with resistance to cancer drugs, particularly those possessing a steroid backbone and gene expression (in concert with other genes involved in cholesterol metabolism) was found to be regulated by sterols. Moreover, in macrophages ABCA2 is influenced by sterols and has a role in regulating cholesterol sequestration, potentially important in cardiovascular disease. Accumulating data indicate the critical importance of ABCA2 in mediating movement of sphingolipids within cellular compartments and these have been implicated in various aspects of cholesterol trafficking. Perhaps because the functions of ABCA2 are linked with membrane building blocks, there are reports linking it with human pathologies, including, cholesterolemias and cardiovascular disease, Alzheimer's and cancer. The present review addresses whether there is now sufficient information to consider ABCA2 as a plausible therapeutic target.
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Affiliation(s)
- Warren Davis
- Dept. of Cell & Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, BSB, MSC 509, Charleston, SC 29425, United States
| | - Kenneth D Tew
- Dept. of Cell & Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, BSB, MSC 509, Charleston, SC 29425, United States.
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29
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Lin GL, Ting HJ, Tseng TC, Juang V, Lo YL. Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells. PLoS One 2017; 12:e0185625. [PMID: 28968471 PMCID: PMC5624618 DOI: 10.1371/journal.pone.0185625] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 09/15/2017] [Indexed: 01/29/2023] Open
Abstract
HuR (ELAVL1), a RNA-binding protein, plays a key role in posttranscriptional regulation of multidrug resistance (MDR)-related genes. Among various HuR-regulated oncogenic transcripts, the activation of galectin-3/β-catenin survival pathway is critical to induce transcription of cyclin D1, P-glycoprotein (P-gp) and/or multidrug resistance-associated proteins (MRPs). In this study, we aim to elucidate the HuR-regulating pathways related to epirubicin-mediated resistance in human colorectal carcinoma cells. The effects and mechanisms of epirubicin treatment on the expressions of upstream survival signals (e.g., β-catenin) and downstream MDR transporters (e.g., P-gp) and anti-apoptotic pathways (e.g., Bcl-2) were assessed with or without HuR knockdown (siHuR) or overexpression (overHuR; ectopic HuR or pcDNA3/HA-HuR). Our results showed that siHuR decreased transcriptional expressions of galectin-3, β-catenin, cyclin D1, Bcl-2, P-gp, MRP1, and MRP2 in epirubicin-treated colon cancer cells. Consistently, the co-treatment of epirubicin and siHuR diminished the expressions of galectin-3, ß-catenin, c-Myc, P-gp and MRP1. HuR silencing enhanced the intracellular accumulation of epirubicin in colon cancer cells. On the other hand, overHuR abolished such effects. Furthermore, siHuR significantly intensified epirubicin-mediated apoptosis via increasing reactive oxygen species and thus promoted the cytotoxic effect of epirubicin. The combined treatments of siHuR and epirubicin significantly reduced the expression of Bcl-2, but increased the expression of Bax, as well as activity and expression levels of caspase-3 and -9. In contrast, overHuR abrogated these effects. Our findings provide insight into the mechanisms by which siHuR potentiated epirubicin-induced cytotoxicity via inhibiting galectin-3/β-catenin signaling, suppressing MDR transporters and provoking apoptosis. To our best knowledge, this is an innovative investigation linking the post-transcriptional control by HuR silencing to survival signaling repression, efflux transporter reversal and apoptosis induction. Our study thus provides a powerful regimen for circumventing MDR in colon cancer cells.
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Affiliation(s)
- Guan-Liang Lin
- Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan
| | - Huei-Ju Ting
- Department of Biological Sciences and Technology, National University of Tainan, Tainan, Taiwan
| | - Ta-Chien Tseng
- Institute of Bioinformatics and Biosignaling Transduction, National Cheng Kung University, Tainan, Taiwan
| | - Vivian Juang
- Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | - Yu-Li Lo
- Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
- * E-mail:
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30
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Zhu Z, Meng W, Liu P, Zhu X, Liu Y, Zou H. DNA hypomethylation of a transcription factor binding site within the promoter of a gout risk gene NRBP1 upregulates its expression by inhibition of TFAP2A binding. Clin Epigenetics 2017; 9:99. [PMID: 28932319 PMCID: PMC5603049 DOI: 10.1186/s13148-017-0401-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 09/05/2017] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Genome-wide association studies (GWASs) have identified dozens of loci associated with gout, but for most cases, the risk genes and the underlying molecular mechanisms contributing to these associations are unknown. This study sought to understand the molecular mechanism of a common genetic variant, rs780093, in the development of gout, both in vitro and in vivo. RESULTS Nuclear receptor binding protein 1 (NRBP1), as a gout risk gene, and its regulatory region, 72 bp upstream of the transcription start site, designated as B1, were identified through integrative analyses of genome-wide genotype and DNA methylation data. We observed elevated NRBP1 expression in human peripheral blood mononuclear cells (PBMCs) from gout patients. In vitro luciferase reporter and protein pulldown assay results showed that DNA methylation could increase the binding of the transcription factor TFAP2A to B1, leading to suppressed gene expression. There results were further confirmed by in vivo bisulfite pyrosequencing showing that hypomethylation on B1 is associated with increased NRBP1 expression in gout patients. CONCLUSIONS Hypomethylation at the promoter region of NRBP1 reduces the binding of TFAP2A and thus leads to elevated NRBP1 expression, which might contribute to the development of gout.
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Affiliation(s)
- Zaihua Zhu
- Division of Rheumatology and Immunology, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China
| | - Weida Meng
- The Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Peiru Liu
- The Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiaoxia Zhu
- Division of Rheumatology and Immunology, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China
| | - Yun Liu
- The Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hejian Zou
- Division of Rheumatology and Immunology, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China
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31
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Hu T, Li Z, Gao CY, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol 2017. [PMID: 27570424 DOI: 10.3748/wjg.vss.i30.6876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.
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Affiliation(s)
- Tao Hu
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Zhen Li
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Chun-Ying Gao
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Chi Hin Cho
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
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32
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Luo W, Xin Y, Zhao X, Zhang F, Liu C, Fan H, Xi T, Xiong J. Suppression of carboxylesterases by imatinib mediated by the down-regulation of pregnane X receptor. Br J Pharmacol 2017; 174:700-717. [PMID: 28128444 DOI: 10.1111/bph.13731] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 01/20/2017] [Accepted: 01/20/2017] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND AND PURPOSE Imatinib mesylate (IM) is a first-line treatment for chronic myeloid leukaemia (CML) as a specific inhibitor of BCR-ABL tyrosine kinase. As IM is widely used in CML, in combination with other drugs, the effects of IM on drug-metabolizing enzymes (DMEs) are crucial to the design of rational drug administration. Carboxylesterases (CESs) are enzymes catalysing the hydrolytic biotransformation of several clinically useful drugs. Although IM is known to inhibit cytochromes P450 (CYPs), its effects on DMEs, and CESs in particular, are still largely undefined. EXPERIMENTAL APPROACH Hepatoma cell lines (HepG2 and Huh7) and primary mouse hepatocytes were used. mRNA and protein expression were evaluated by quantitative RT-PCR and Western blot analysis. Reporter luciferase activity was determined by transient co-transfection experiment. Pregnane X receptor (PXR) expression was regulated by overexpression and RNA interference. The activity of CESs was determined by enzymic and toxicological assays. Mice were treated with a range of doses of IM to analyse expression of CESs in mouse liver. KEY RESULTS The expression and activity of CESs were markedly repressed by IM, along with the down-regulation of PXR and inhibited expression and activity of CYP3A4 and P-gp. CONCLUSIONS AND IMPLICATIONS Down-regulation of PXR mediates IM-induced suppression of CESs. IM may inhibit expression of other genes targeted by PXR, thus inducing a wide range of potential drug-drug interactions during treatment of CML. The data deserve further elucidation including clinical trials.
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Affiliation(s)
- Wenjing Luo
- Department of Pharmacology, Nanjing Medical University, Nanjing, China.,Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yu Xin
- Department of Pharmacology, Nanjing Medical University, Nanjing, China.,Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Xia Zhao
- Department of Pharmacy, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, China
| | - Feng Zhang
- Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Changqing Liu
- Clinical Pharmacology Laboratory, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Hongwei Fan
- Clinical Pharmacology Laboratory, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Tao Xi
- Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Jing Xiong
- Department of Pharmacology, Nanjing Medical University, Nanjing, China
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Abstract
Wnt (Wingless-related integration site)-signaling orchestrates self-renewal programs in normal somatic stem cells as well as in cancer stem cells. Aberrant Wnt signaling is associated with a wide variety of malignancies and diseases. Although our understanding has increased tremendously over the past decade, therapeutic targeting of the dysregulated Wnt pathway remains a challenge. Here we review recent preclinical and clinical therapeutic approaches to target the Wnt pathway.
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34
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Ma Y, Miao Y, Peng Z, Sandgren J, De Ståhl TD, Huss M, Lennartsson L, Liu Y, Nistér M, Nilsson S, Li C. Identification of mutations, gene expression changes and fusion transcripts by whole transcriptome RNAseq in docetaxel resistant prostate cancer cells. SPRINGERPLUS 2016; 5:1861. [PMID: 27822437 PMCID: PMC5078122 DOI: 10.1186/s40064-016-3543-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 10/13/2016] [Indexed: 12/18/2022]
Abstract
Docetaxel has been the standard first-line therapy in metastatic castration resistant prostate cancer. The survival benefit is, however, limited by either primary or acquired resistance. In this study, Du145 prostate cancer cells were converted to docetaxel-resistant cells Du145-R and Du145-RB by in vitro culturing. Next generation RNAseq was employed to analyze these cell lines. Forty-two genes were identified to have acquired mutations after the resistance development, of which thirty-four were found to have mutations in published sequencing studies using prostate cancer samples from patients. Fourteen novel and 2 previously known fusion genes were inferred from the RNA-seq data, and 13 of these were validated by RT-PCR and/or re-sequencing. Four in-frame fusion transcripts could be transcribed into fusion proteins in stably transfected HEK293 cells, including MYH9-EIF3D and LDLR-RPL31P11, which were specific identified or up-regulated in the docetaxel resistant DU145 cells. A panel of 615 gene transcripts was identified to have significantly changed expression profile in the docetaxel resistant cells. These transcriptional changes have potential for further study as predictive biomarkers and as targets of docetaxel treatment.
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Affiliation(s)
- Yuanjun Ma
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Yali Miao
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden ; Department of Obstetrics and Gynecology, Beijing University People's Hospital, Beijing, China
| | - Zhuochun Peng
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Johanna Sandgren
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | | | - Mikael Huss
- SciLifeLab (Science for Life Laboratory), Stockholm, Sweden
| | - Lena Lennartsson
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Yanling Liu
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Monica Nistér
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden ; Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden
| | - Sten Nilsson
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden ; Department of Clinical Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Chunde Li
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden ; Department of Clinical Oncology, Karolinska University Hospital, Stockholm, Sweden
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35
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Garcia-Recio M, Martinez-Serra J, Bento L, Ramos R, Gines J, Daumal J, Sampol A, Gutierrez A. Lenalidomide, celecoxib, and azacitidine therapy for blastic plasmocytoid dendritic cell neoplasm: a case report. Onco Targets Ther 2016; 9:5507-11. [PMID: 27660468 PMCID: PMC5019433 DOI: 10.2147/ott.s107893] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Blastic plasmocytoid dendritic cell neoplasm is characterized by aggressive behavior with a tendency for systemic dissemination and a predilection for skin, lymph nodes, soft tissues, peripheral blood, or bone marrow. It usually occurs in elderly patients with a mean age between 60 and 70 years. Despite initial response to chemotherapy, the disease regularly relapses with a short median overall survival. Better outcomes have been reported with high-dose acute leukemia-like induction chemotherapy followed by consolidation with allogeneic hematopoietic stem cell transplantation. However, elderly patients are not candidates for intensive therapy or allogeneic stem cell transplantation. So, new active and tolerable drugs are needed. Our case illustrates that one cycle of lenalidomide and celecoxib provides at least a partial cutaneous and hematologic response, but this regimen was discontinued due to toxicity and followed by a consolidation/maintenance phase with azacitidine, thus achieving a final complete response with a much higher than expected progression-free and overall survival in an elderly patient with comorbidities. This information may be useful in the design of treatment approaches for elderly patients with blastic plasmocytoid dendritic cell neoplasm. However, it should be confirmed in clinical trials as well as by optimizing the induction and extending the consolidation/maintenance period to avoid early relapses after discontinuation and improve progression-free survival.
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Affiliation(s)
- Marta Garcia-Recio
- Service of Hematology; Instituto de Investigación Sanitaria de Palma (IdISPa)
| | | | - Leyre Bento
- Service of Hematology; Instituto de Investigación Sanitaria de Palma (IdISPa)
| | - Rafael Ramos
- Instituto de Investigación Sanitaria de Palma (IdISPa); Service of Pathology
| | | | - Jaime Daumal
- Service of Nuclear Medicine, Son Espases University Hospital, Palma de Mallorca, Spain
| | - Antonia Sampol
- Service of Hematology; Instituto de Investigación Sanitaria de Palma (IdISPa)
| | - Antonio Gutierrez
- Service of Hematology; Instituto de Investigación Sanitaria de Palma (IdISPa)
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36
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Hu T, Li Z, Gao CY, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol 2016; 22:6876-6889. [PMID: 27570424 PMCID: PMC4974586 DOI: 10.3748/wjg.v22.i30.6876] [Citation(s) in RCA: 267] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/24/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open
Abstract
Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.
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37
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A Second WNT for Old Drugs: Drug Repositioning against WNT-Dependent Cancers. Cancers (Basel) 2016; 8:cancers8070066. [PMID: 27429001 PMCID: PMC4963808 DOI: 10.3390/cancers8070066] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 06/24/2016] [Accepted: 07/07/2016] [Indexed: 12/21/2022] Open
Abstract
Aberrant WNT signaling underlies cancerous transformation and growth in many tissues, such as the colon, breast, liver, and others. Downregulation of the WNT pathway is a desired mode of development of targeted therapies against these cancers. Despite the urgent need, no WNT signaling-directed drugs currently exist, and only very few candidates have reached early phase clinical trials. Among different strategies to develop WNT-targeting anti-cancer therapies, repositioning of existing drugs previously approved for other diseases is a promising approach. Nonsteroidal anti-inflammatory drugs like aspirin, the anti-leprotic clofazimine, and the anti-trypanosomal suramin are among examples of drugs having recently revealed WNT-targeting activities. In total, 16 human-use drug compounds have been found to be working through the WNT pathway and show promise for their prospective repositioning against various cancers. Advances, hurdles, and prospects of developing these molecules as potential drugs against WNT-dependent cancers, as well as approaches for discovering new ones for repositioning, are the foci of the current review.
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38
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Knapp DW, Ruple-Czerniak A, Ramos-Vara JA, Naughton JF, Fulkerson CM, Honkisz SI. A Nonselective Cyclooxygenase Inhibitor Enhances the Activity of Vinblastine in a Naturally-Occurring Canine Model of Invasive Urothelial Carcinoma. Bladder Cancer 2016; 2:241-250. [PMID: 27376143 PMCID: PMC4927831 DOI: 10.3233/blc-150044] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background: Chemotherapy is expected to remain an important part of invasive urothelial carcinoma (UC) treatment. Strategies to enhance chemotherapy efficacy are needed. Objective: To determine the chemotherapy-enhancing effects of a nonselective cyclooxygenase (COX) inhibitor on vinblastine in a naturally-occurring canine model of invasive UC. Methods: With IACUC approval, privately-owned dogs with naturally-occurring histologically-diagnosed invasive UC, expected survival ≥6 weeks, and informed owner consent were randomly allocated to receive vinblastine (2.5 mg/m2 intravenously every 2 weeks) plus piroxicam (0.3 mg/kg daily per os) or vinblastine alone (same dose) with the option to receive piroxicam alone when vinblastine failed. Scheduled evaluations included physical exam, standard laboratory analyses, thoracic radiography, abdominal ultrasonography, and standardized measurement of urinary tract tumors. Results: Dogs receiving vinblastine alone (n = 27) and vinblastine-piroxicam (n = 24) were similar in age, sex, breed, tumor stage, and grade. Remission occurred more frequently (P < 0.02) with vinblastine-piroxicam (58.3%) than with vinblastine alone (22.2%). The median progression free interval was 143 days with vinblastine alone and 199 days with the combination. Interestingly, the overall median survival time was significantly longer (P < 0.03) in dogs receiving vinblastine alone followed by piroxicam alone (n = 20, 531 days) than in dogs receiving the combination (299 days). Treatment was well tolerated in both arms. Conclusions: Piroxicam significantly enhanced the activity of vinblastine in dogs with UC where the cancer closely mimics the human condition, clearly justifying further study. The study suggest the potential importance of tracking COX inhibitor use in patients in clinical trials as COX inhibitors could affect treatment response.
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Affiliation(s)
- Deborah W Knapp
- Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, USA; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA
| | | | - José A Ramos-Vara
- Department of Comparative Pathobiology, Purdue University , West Lafayette, IN, USA
| | | | | | - Sonia I Honkisz
- Department of Veterinary Clinical Sciences, Purdue University , West Lafayette, IN, USA
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CHEN JIERU, JIA XIUHONG, WANG HONG, YI YINGJIE, WANG JIANYONG, LI YOUJIE. Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway. Int J Oncol 2016; 48:2063-70. [DOI: 10.3892/ijo.2016.3423] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 02/14/2016] [Indexed: 11/06/2022] Open
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Synergistic cytotoxicity from combination of imatinib and platinum-based anticancer drugs specifically in Bcr-Abl positive leukemia cells. J Pharmacol Sci 2015; 129:210-5. [DOI: 10.1016/j.jphs.2015.10.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 10/14/2015] [Accepted: 10/26/2015] [Indexed: 11/23/2022] Open
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Szwed M, Kania KD, Jozwiak Z. Toxicity of doxorubicin-transferrin conjugate is connected to the modulation of Wnt/β-catenin pathway in human leukemia cells. Leuk Res 2015; 39:1096-102. [DOI: 10.1016/j.leukres.2015.07.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 06/26/2015] [Accepted: 07/09/2015] [Indexed: 01/17/2023]
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