β-elemene Sensitizes Hepatocellular Carcinoma Cells to Oxaliplatin by Preventing Oxaliplatin-induced Degradation of Copper Transporter 1

β-elemene, a Curcuma wenyujin plant extract, has been used widely as a tumor adjuvant therapeutic agent. However, how to obtain optimum therapeutic effects by combining this compound with other agents remain unclear. In this study, we found that β-elemene, which alone had little effect on hepatocellular carcinoma (HCC) cell proliferation, exerted a synergistic anti-proliferative effect in HCC cells when dosed in combination with oxaliplatin, which increased the amounts of platinum accumulation and platinum-DNA adduct significantly and augmented the oxaliplatin-induced apoptosis. Western blot and laser scanning confocal microscopy studies indicated that β-elemene enhanced the sensitivity of HCC cells to oxaliplatin by upregulating copper transporter 1 (CTR1), a major controller of intracellular platinum accumulation. In an orthotopic transplantation HCC model in nude mice, HCC tumor growth was inhibited significantly by oxaliplatin combined with β-elemene, as compared with oxaliplatin alone. Notably, CTR1 protein expression in xenograft HCC was upregulated in mice who received β-elemene treatment. Taken together, our findings show that β-elemene can block the reduction of CTR1 resulting from oxaliplatin treatment, and therefore has a synergistic anti-HCC effect with oxaliplatin by enhancing cellular uptake of oxaliplatin. The synergistic effects of β-elemene and oxaliplatin deserve further evaluation in clinical settings.