Abstract
{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)/p22phox, Sirtuin3 (SIRT3)/SOD2, and SIRT3/p53/p21Waf1/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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies due to difficulty of early detection and chemoresistance [1]
We suggested that methyl-ethyl]-1H-indol-3-yl}-acetic acid methyl ester (MIAM) might inhibit cancer growth through intercalating to DNA suppressing topoisomerase activity like ADR [14]
A significant difference was observed between Bel-7402/5FU and Bel-7402 (P < 0.05). These results indicated that MIAM inhibited HCC growth more potential in Bel-7402/5FU cells than its parent cells
Summary
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies due to difficulty of early detection and chemoresistance [1]. SIRT3 has been found to play important roles in maintaining mitochondrial function and integrity in response to the oxidative stress. SIRT3 involves in metabolism, ATP generation, and oxidative stress by deacetylasing lysine residues of mitochondrial proteins [4, 5]. High expression of SIRT3 has been considered to suppress HCC growth, invasion, and acquired resistance [6, 7]. Deletion of SIRT3 in mouse embryonic fibroblasts exhibited the phenotype of high proliferation, antiapoptosis, and the characteristic of invasion and metastasis [11]. Cancer cells with deletion of SIRT3 might result in antiapoptotic phenotype through the mechanism of preventing the Bak- or Bax-induced mitochondrial damage [12, 13]. SIRT3 has been considered to be an important target for design and use of chemotherapeutic drugs
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