1. HDAC inhibitors downregulate MRP2 expression in multidrug resistant cancer cells: implication for chemosensitization.
- Author
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Kim H, Kim SN, Park YS, Kim NH, Han JW, Lee HY, and Kim YK
- Subjects
- Antineoplastic Agents pharmacology, Cell Line, Tumor, Dose-Response Relationship, Drug, Down-Regulation drug effects, Down-Regulation genetics, Drug Evaluation, Preclinical, Drug Resistance, Multiple drug effects, Drug Resistance, Neoplasm drug effects, Drug Synergism, Gene Expression Regulation, Neoplastic drug effects, Humans, Hydroxamic Acids pharmacology, Multidrug Resistance-Associated Protein 2, Multidrug Resistance-Associated Proteins metabolism, Multidrug Resistance-Associated Proteins physiology, Neoplasms metabolism, Neoplasms pathology, Paclitaxel pharmacokinetics, Paclitaxel pharmacology, Vorinostat, Drug Resistance, Multiple genetics, Drug Resistance, Neoplasm genetics, Histone Deacetylase Inhibitors pharmacology, Multidrug Resistance-Associated Proteins genetics, Neoplasms genetics
- Abstract
Although histone deacetylase (HDAC) inhibitors are emerging as a promising class of cancer chemotherapeutic agents, their effects on multidrug resistance (MDR) are poorly understood. In this study, we investigated whether HDAC inhibitors overcome MDR phenotype. HDAC inhibitors suppress the growth of both MDR positive cancer cells KBV20C and its parental cells KB with similar potencies. In parallel, histone acetylation and p21WAF1 expression by the HDAC inhibitors were similarly increased in both cell types, indicating that these HDAC inhibitors are poor substrates of ABC drug transporters and effective in MDR cancer cells. In addition, multidrug resistance protein 2 (MRP2) expression is selectively attenuated by HDAC inhibitors, especially SAHA and TSA, in KBV20C cells, whereas MDR1 and BCRP expressions are not affected. This downregulation of MRP2 contributes to increase in paclitaxel-induced G2/M arrest and apoptosis, which might be due to intracellular accumulation of paclitaxel. Collectively, our data provide a molecular rationale for the application of HDAC inhibitors to overcome MDR in cancer cells.
- Published
- 2011
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