대장암 치료에서의 기존 항암제와 HDAC6 inhibitor와의 combination therapy에 대한 연구

Dept. of Pharmacy/석사Histone deacetylase 6 (HDAC6), the best-characterized class IIb histone deacetylase, is a cytoplasmic enzyme that regulates many important biological processes. HDAC inhibitors (HDACI) are promising therapeutic agents which are currently used in combination with chemotherapeutic agents in clinical trials for cancer treatment. Here we show that a γ–lactam based HDAC inhibitor A452 selectively inhibits HDAC6 catalytic activity in vivo and in vitro. A452 causes cell death as well as growth inhibition of transformed cells (HCT116, HT29, LNCaP, MCF, A549) an effect not observed in normal cells (BJ). Interestingly, A452 exhibits differential cytotoxicity for wild type and mutant p53 human colon cancer cells. A452 shows different mechanisms of action of modulating p53: A452 increases wild type p53 by destabilizing Mdm2 while decrease mutant p53 by stabilizing Mdm2 in colon cancer cells. Moreover, A452 significantly enhances cell death induced by the topoisomerase I inhibitor irinotecan, DNA synthesis inhibitor capecitabine (a prodrug of 5-fluorouracil) and the pan-HDAC inhibitor SAHA in colon cancer cells. A452 in combination with irinotecan, capecitabine or SAHA is more potent than either drug alone in the apoptotic pathway, as evidenced by an increase in PARP cleavage. Furthermore, A452 enhances DNA damage induced by irinotecan, capecitabine or SAHA as indicated by increased accumulation of H2AX and activation of the checkpoint kinase Chk2. However, A452 does not increase cisplatin-induced cytotoxicity in HCT116 and HT29 cells. Therefore, these findings indicate that A452 is a specific HDAC6 inhibitor and point mechanism by which HDAC6-selective inhibition can enhance the efficacy of certain anti-cancer agents in colon cancer cells.ope