{2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-
acetic acid methyl ester (MIAM) is a novel
indole compound, which possessed high efficacy against many
cancers xenografted in mice without obvious toxicity. In this study, we aimed to investigate the effects of MIAM on human
hepatocellular carcinoma (HCC) Bel-7402 cells and its resistant variants Bel-7402/
5FU. MIAM inhibited the growth of HCC more potent in Bel-7402/
5FU cells than its parent cells. MIAM increased cellular
reactive oxygen species (ROS) levels, induced cell apoptosis, and arrested cell cycle in G0/G1 phase. MIAM might exert its action on Bel-7402/
5FU cells through activation of
NADPH oxidase 4 (NOX4)/p22(
phox), Sirtuin3 (
SIRT3)/SOD2, and
SIRT3/p53/p21(Waf1/Cip) pathways. MIAM might inhibit HCC growth through the modulation of
SIRT3. When
SIRT3 was silenced, the inhibitory effect of MIAM on Bel-7402/
5FU was lowered, showing the characteristic of resistance against MIAM, whereas Bel-7402/
5FU cells with high expression of
SIRT3 by
SIRT3 adenovirus infection demonstrated the high sensitivity to MIAM. These results suggested that MIAM might exert its action against Bel-7402/
5FU growth through upregulation of
SIRT3. We suggested that MIAM might be a promising candidate compound which could develop as a potent
anticancer agent targeting NOX4 and
SIRT3 activation.