Cytotoxic Effects of Xanthohumol and Its Combination with Cisplatin on Human Metastatic Lung Cancer H1299 Cells

Abstract

Aims: Non-small cell lung cancer (NSCLC) accounts for high lung cancer death that is mostly associated with advanced disease stage at diagnosis and resistance to chemotherapy. In the present study, we investigated whether xanthohumol, a prenylated flavonoid of hop plant, induces metastatic lung cancer H1299 cell death, and whether in combination with cisplatin there are additive effects. Methodology: H1299 cells were grown and treated with xanthohumol (6.25, 12.5, or 25 µM), cisplatin (12.5, 25, or 50 µM) and the combination of cisplatin and xanthohumol for 24 h. Cell viability, cell morphology, chromatin condensation, ɣH2AX, cPARP-1, capsase-3, p21WAF1/CIP1 and p14ARF genes were analyzed. Results: Xanthohumol, cisplatin, and the combination of cisplatin and xanthohumol inhibited H1299 cells viability.  Cisplatin growth inhibitory effects were potentiated by xanthohumol.  Xanthohumol induced chromatin condensation and apoptosis and potentiated cisplatin’s effect vs cisplatin alone. Further investigation of growth inhibitory effects, xanthohumol alone induced γH2AX foci formation and the combination potentiated γH2AX foci formation. Cisplatin, xanthohumol at 25 μM, and the combination of cisplatin and xanthohumol at 6.25 and 12.5 μM increased cPARP-1 level.  Active caspase-3 was increased by cisplatin, 12.5 μM of xanthohumol, and the combination of xanthohumol and cisplatin. Xanthohumol at 6.25 or 12.5 μM potentiated cisplatin effect on active caspase-3 and cPARP-1, respectively.  Xanthohumol at 25 µM significtly induced the expression cell cycle control genes p21WAF1/CIP1 and p14ARF.  These results indicate that xanthohumol inhibits proliferation of H1299 cells and induces cell death through cleavage of PARP-1 and activation of caspase-3. The combination of cisplatin and xanthohumol potentiated cytotoxic effects of each other compound. Conclusion: The present study suggests that xanthohumol poses apoptotic effects and potentiates cisplatin’s growth inhibitory effects on metastatic lung cancer cells.