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To improve the outcome of cancer chemotherapy, strategies to enhance the efficacy of anticancer drugs are required. Sorafenib is the only drug to prolong overall survival of the patients with hepatocellular carcinoma ( HCC ), however, the outcome is still not satisfactory. Retinoids, vitamin A derivatives, have been known to exhibit inhibitory effects on various cancers including  HCC . In this study, we investigated the effects of combined treatment using sorafenib and retinoids including  all‐trans  retinoic acid ( ATRA ),  NIK ‐333, and Am80 on  HCC  cells. Cell viability assays in six  HCC  cell lines, HepG2,  PLC / PRF /5, HuH6,  HLE ,  HLF , and Hep3B, revealed that 5 and 10 μM  ATRA , concentrations that do not exert cytotoxic effects, enhanced the cytotoxicity of sorafenib, being much more effective than  NIK ‐333 and Am80. We found that  ATRA  induced  AMP ‐activated protein kinase activation, which was followed by reduced intracellular  ATP  level. Gene expression analysis revealed that  ATRA  decreased the expression of glycolytic genes such as   GLUT ‐1  and   LDHA  . In the combination treatment using  ATRA  and sorafenib, increased apoptosis, followed by the activation of p38  MAPK  and  JNK , the upregulation and translocation of Bax to mitochondria, and the activation of caspase‐3, was observed. Suppression of  AMP ‐activated protein kinase by si RNA  restored the viability of the cells treated with  ATRA  and sorafenib. Our results thus indicate that  ATRA  is useful for enhancing the cytotoxicity of sorafenib against  HCC  cells by regulating the energy metabolism of  HCC  cells.

Activation of AMP ‐activated protein kinase by retinoic acid sensitizes hepatocellular carcinoma cells to apoptosis induced by sorafenib