All-trans Retinoic Acid combined with oxaliplatin suppressed proliferation of chemo-resistant hepatocellular carcinoma cells by inducing G2/M cell cycle arrest

Introduction To investigate the effects and mechanisms of all-trans retinoic acid (ATRA) with and without oxaliplatin (OXA) on chemotherapy-resistant hepatocellular carcinoma cell lines. Material and methods OXA-resistant cell lines (CSQT-2-R and Hep3b-R) and subcutaneous xenograft model were used in this study. MTT assay, flow cytometry, crystal violet assay, transwell assay and western-blotting were conducted to evaluate the effects of co-treatment with ATRA and OXA on OXA-resistant HCC in vivo and in vitro. The differences between two groups were analyzed using ANOVA. All statistical tests in the study were two-sided, and statistical significance was set at P<0.05. Results We established two oxaliplatin-Resistant HCC cell lines (CSQT-2-R and Hep3b-R). The drug resistance ability can be increased up to 100% than their parental cells(CSQT-2 and Hep3b) in certain concentration of OXA. ATRA alone could not inhibited the viability of CSQT-2-R and Hep3b-R, but it can enhance the ability of OXA on apoptosis than OXA alone (75% vs 35%, p<0.05), which may be related to decreased p-AKT expression. Moreover, the co-treatment of two drugs arrest the cell cycle of OXA-resistant cell at G2/M phase by up-regulating CylinB1 protein. Conclusions ATRA combined with OXA can elicit cell cycle arrest of CSQT-2-R and Hep3b-R at G2/M phase, thereby inhibiting the proliferation of resistant HCC cell, which provides a new treatment for chemotherapy-resistant HCC.