α-Humulene inhibits hepatocellular carcinoma cell proliferation and induces apoptosis through the inhibition of Akt signaling

Hepatocellular carcinoma (HCC) is a prevalent malignancy and a leading cause of cancer-related mortality. alpha-Humulene (HML) is a natural 11-membered monocyclic terpene with three E-configured double bonds isolated from Eupatorium odoratum L. We recently showed that HML has significant anti-HCC activity in vitro and in vivo. We found that HML was cytotoxic to HCC cells and induced mitochondrial apoptosis of HCC cells, promoting caspase-3 activation and PARP cleavage. HCC cells show abnormal Akt signaling to resist apoptosis. Mechanistically, HML was found to inhibit Akt activation, subsequently decreasing GSK-3 and Bad phosphorylation, promoting apoptotic induction. HML also inhibited cell proliferation and enhanced apoptosis in HCC tumor xenografts further highlighting its activity in vivo. Although HML showed minimal cytotoxicity to normal hepatocytes, weight loss was observed in mice administered HML. Taken together, these data provide important and novel insights into the anti-HCC effects of HML through its ability to inhibit Akt, reduced HCC cell proliferation, and enhanced HCC cell apoptotic induction in vitro and in vivo.