Abstract
Despite improvement in therapeutic strategies, median survival in advanced hepatocellular carcinoma (HCC) remains less than one year. Therefore, molecularly targeted compounds with less toxic profiles are needed. Xanthohumol (XN), a prenylated chalcone has been shown to have anti-proliferative effects in various cancers types in vitro. XN treatment in healthy mice and humans yielded favorable pharmacokinetics and bioavailability. Therefore, we determined to study the effects of XN and understand the mechanism of its action in HCC. The effects of XN on a panel of HCC cell lines were assessed for cell viability, colony forming ability, and cellular proliferation. Cell lysates were analyzed for pro-apoptotic (c-PARP and cleaved caspase-3) and anti-apoptotic markers (survivin, cyclin D1, and Mcl-1). XN concentrations of 5μM and above significantly reduced the cell viability, colony forming ability and also confluency of all four HCC cell lines studied. Furthermore, growth suppression due to apoptosis was evidenced by increased expression of pro-apoptotic and reduced expression of anti-apoptotic proteins. Importantly, XN treatment inhibited the Notch signaling pathway as evidenced by the decrease in the expression of Notch1 and HES-1 proteins. Ectopic expression of Notch1 in HCC cells reverses the anti-proliferative effect of XN as evidenced by reduced growth suppression compared to control. Taken together these results suggested that XN mediated growth suppression is appeared to be mediated by the inhibition of the Notch signaling pathway. Therefore, our findings warrants further studies on XN as a potential agent for the treatment for HCC.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally [1]
We examined the anti-proliferative effects of XN on established human hepatocellular carcinoma (HCC) cell lines
Ectopic expression of Notch1 reversed XN-induced suppression in HCC cells. These findings suggest that the mechanism by which HCC cellular proliferation is reduced following XN treatment appears to be mediated by the inhibition of the Notch signaling pathway
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally [1]. 70% of patients present with advanced disease often with concomitant cirrhosis. The 5-year survival for these patients is 50–70%[1]. The single effective curative modality is surgical resection; given the metastatic potential and PLOS ONE | DOI:10.1371/journal.pone.0127464. Notch Signaling and Hepatocellular Carcinoma comorbidities surrounding patients with HCC, surgery is often non-efficacious. Palliative care is often the mainstay of treatment strategies. Sorafenib has a limited survival advantage of approximately 11 weeks and is effective in nearly one-third of patients [2, 3]. Given the increasing understanding of signaling pathways and the limited treatment options to date, the development of new therapeutic strategies is integral [4, 5]
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