Reversal of P-glycoprotein (P-gp) mediated multidrug resistance in colon cancer cells by cryptotanshinone and dihydrotanshinone of Salvia miltiorrhiza |
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| Institution: | 1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;2. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;1. Key Laboratory of Digital Quality Evaluation of Chinese Materia Medical of State Administration of TCM, China, Engineering & Technology Research Center for Chines Materia Medical Quality of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China;2. School of Chinese Medicine, Southern Medical University, Guangzhou 510515, China;1. Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421 Homburg, Germany;2. Dept of Drug Delivery, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Center for Infection Research, Saarland University, 66123 Saarbrücken, Germany;1. Science and Technology Unit (STU), Umm Al-Qura University, Makkah, 21955, Saudi Arabia;2. Central Laboratory for Micro-analysis, Minia University, Minia, 61519, Egypt;3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura University, Makkah, 21955, Saudi Arabia;4. Departmentof Pharmacology and Toxicology, Medicinal and Aromatic Plants Research Institute, National Center for Research, Khartoum, 2404, Sudan;5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah, 21955, Saudi Arabia;6. Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt;7. Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, 21955, Saudi Arabia;8. Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt;1. Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China;2. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China;3. Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China;1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Nan Jing Research and Development Center, CTTQ Pharmaceutical Research Institute, Building 9, NO. 699-8, Xuanwu Dadao, Xuanwu District, Nanjing, Jiangsu, PR China |
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| Abstract: | ObjectiveMultidrug resistance (MDR) of cancer cells to a broad spectrum of anticancer drugs is an obstacle to successful chemotherapy. Overexpression of P-glycoprotein (P-gp), an ATP-binding cassette (ABC) membrane transporter, can mediate the efflux of cytotoxic drugs out of cancer cells, leading to MDR and chemotherapy failure. Thus, development of safe and effective P-gp inhibitors plays an important role in circumvention of MDR. This study investigated the reversal of P-gp mediated multidrug resistance in colon cancer cells by five tanshinones including tanshinone I, tanshinone IIA, cryptotanshinone, dihydrotanshinone and miltirone isolated from Salvia miltiorrhiza (Danshen), known to be safe in traditional Chinese medicine.MethodsThe inhibitory effects of tanshinones on P-gp function were compared using digoxin bi-directional transport assay in Caco-2 cells. The potentiation of cytotoxicity of anticancer drugs by effective tanshinones were evaluated by MTT assay. Doxorubicin efflux assay by flow cytometry, P-gp protein expression by western blot analysis, immunofluorescence for P-gp by confocal microscopy, quantitative real-time PCR and P-gp ATPase activity assay were used to study the possible underlying mechanisms of action of effective tanshinones.ResultsBi-directional transport assay showed that only cryptotanshinone and dihydrotanshinone decreased digoxin efflux ratio in a concentration-dependent manner, indicating their inhibitory effects on P-gp function; whereas, tanshinone I, tanshinone IIA and miltirone had no inhibitory effects. Moreover, both cryptotanshinone and dihydrotanshinone could potentiate the cytotoxicity of doxorubicin and irinotecan in P-gp overexpressing SW620 Ad300 colon cancer cells. Results from mechanistic studies revealed that these two tanshinones increased intracellular accumulation of the P-gp substrate anticancer drugs, presumably by down-regulating P-gp mRNA and protein levels, and inhibiting P-gp ATPase activity.ConclusionsTaken together, these findings suggest that cryptotanshinone and dihydrotanshinone could be further developed for sensitizing resistant cancer cells and used as an adjuvant therapy together with anticancer drugs to improve their therapeutic efficacies for colon cancer. |
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| Keywords: | Cryptotanshinone Dihydrotanshinone P-glycoprotein Multidrug resistance |
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