Novel alkoxyamide-based histone deacetylase inhibitors reverse cisplatin resistance in chemoresistant cancer cells |
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| Institution: | 1. Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA;1. Department of Medicine, Mackay Medical College, New Taipei City, Taiwan;2. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan;3. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;4. Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taiwan;5. Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan;6. Division of Urology, Taipei City Hospital HepingFuyou Branch, Taipei, Taiwan;7. Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;1. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji''nan, Shandong, 250012, PR China;2. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji''nan, Shandong, 250012, PR China;3. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, 27710, USA;1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, 250012 Ji’nan, Shandong, PR China;2. School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji’nan, Shandong, PR China |
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| Abstract: | Although histone deacetylase inhibitors (HDACi) have shown promising antitumor effects in specific types of blood cancer, their effects on solid tumors are limited. Previously, we developed LMK235 (5), a class I and class IIb preferential HDACi with chemosensitizing effects on breast cancer, ovarian cancer and HNSCC. Based on its promising effects on solid tumor cells, we modified the cap group of 5 to improve its anticancer activity. The tri- and dimethoxy-phenyl substituted compounds 13a and 13d turned out to be the most potent HDAC inhibitors of this study. The isoform profiling revealed a dual HDAC2/HDAC6 inhibition profile, which was confirmed by the acetylation of α-tubulin and histone H3 in Cal27 and Cal27CisR. In combination with cisplatin, both compounds enhanced the cisplatin-induced cytotoxicity via caspase-3/7 activation. The effect was more pronounced in the cisplatin resistant subline Cal27CisR. The pretreatment with 13d resulted in a complete resensitisation of Cal27CisR with IC50 values in the range of the parental cell line. Therefore, 13d may serve as an epigenetic tool to analyze and modulate the cisplatin resistance of solid tumors. |
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| Keywords: | Histone deacetylases Cisplatin resistance Chemosensitizing effects HATU"} {"#name":"keyword" "$":{"id":"k0025"} "$$":[{"#name":"text" "_":"Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium MTT"} {"#name":"keyword" "$":{"id":"k0035"} "$$":[{"#name":"text" "_":"3-(4 5-Dimethylthiazole-2-yl)-2 5-diphenyltetrazoliumbromide |
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