Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive neoplasm. We aim to explore the anti-HCC activity by a natural prenylflavonoid icaritin. Icaritin was cytotoxic and pro-apoptotic when added to established (HepG2, KYN-2 and Huh-7 lines) and primary human HCC cells. At the signaling level, icaritin inhibited sphingosine kinase 1 (SphK1) activity in HCC cells, which led to pro-apoptotic ceramide production and JNK1 activation. SphK1 inhibition or silence (by shRNA/microRNA) mimicked icaritin-mediated cytotoxicity, and almost nullified icaritin's activity in HepG2 cells. Reversely, exogenous over-expression of SphK1 sensitized icaritin-induced HepG2 cell apoptosis. In vivo, oral administration of icaritin dramatically inhibited HepG2 xenograft growth in SCID mice. Further, SphK1 activity in icaritin-treated tumors was largely inhibited. In summary, icaritin exerts potent anti-HCC activity in vitro and in vivo. SphK1 inhibition could be the primary mechanism of its actions in HCC cells.
Highlights
Hepatocellular carcinoma (HCC) is a major health problem worldwide, in China and other Eastern countries [1, 2]
We here explored the potential effect of icaritin against HCC cells
Icaritin was cytotoxic to two other human HCC cell lines: Huh-7 and KYN-2 (Figure 1F)
Summary
Hepatocellular carcinoma (HCC) is a major health problem worldwide, in China and other Eastern countries [1, 2]. Clinical treatments for HCC have achieved significant progresses, yet surgical resection remains to be the only curative therapy [1, 2]. Many HCC patients are diagnosed at advanced stages when surgery is no longer applicable [1, 2]. A number of early-stage HCC patients will develop cancer recurrences or metastasis following hepatectomy [1, 2]. HCC shows only weak response to the traditional chemotherapeutic drugs, possibly due to its high level of pre-existing or acquired resistances [1,2,3]. Molecule-targeted therapy is being tested in preclinical and clinical HCC studies [4, 5]. Sorafenib is the only agent approved for the systemic treatment of HCC [6, 7]. There is an urgent need to explore other novel anti-HCC agents [4, 5]
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