To investigate the anticancer effects of the novel
hydroxamic acid-derived
histone deacetylase (
HDAC) inhibitor MHY218, its efficacy was compared to that of
suberoylanilide hydroxamic acid (SAHA) in human
ovarian cancer cells. The anticancer effects of
MHY218 on cell viability, cell cycle regulation and apoptosis were investigated. In addition,
MHY218 or SAHA was administered for 28 days in a
tumor carcinomatosis model with SKOV-3 cells.
MHY218 significantly reduced the expression of HDAC4 and HDAC7 in SKOV-3 cells. Similarly,
MHY218 also inhibited total HDAC, HDAC1, HDAC4 and HDAC7
enzyme activity in a concentration-dependent manner. The anticancer effect of
MHY218 (IC50, 3.2 microM) was more potent than SAHA (IC50, 3.9 microM) in suppressing the SKOV-3 cell viability. Moreover,
MHY218 markedly increased expression of p21WAF1/CIP1, which acts as a cell cycle inhibitor. Cell cycle analysis showed that the high dose (5 microM) of
MHY218 significantly increased the proportion of cells in the G2/M phase. In particular,
MHY218 and SAHA significantly increased the sub-G1 population and the number of TUNEL-positive apoptotic cells compared with those in the untreated control. These results were confirmed by analysis of
poly-ADP ribose polymerase (PARP), where
MHY218 and SAHA increased the level of an 85-kDa fragment resulting from PARP cleavage as well as
caspase-3 activity. Likewise, MHY218-induced apoptosis through
caspase-3 activation was confirmed by the increase in the release of
cytochrome c and Bax/Bcl-2 ratio. In an in vivo
tumor carcinomatosis model, the growth of transplanted SKOV-3 cells was inhibited by 71%
after treatment with
MHY218 (10 mg/kg), whereas SAHA (25 mg/kg) suppressed growth by 48%. These results indicate that
MHY218 is a potent
HDAC inhibitor that targets regulating multiple aspects of
cancer cell death and might have preclinical value in
ovarian cancer chemotherapy, warranting further investigation.