Therapeutic targeting of hepatocellular carcinoma cells with antrocinol, a novel, dual-specificity, small-molecule inhibitor of the KRAS and ERK oncogenic signaling pathways

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Title:	Therapeutic targeting of hepatocellular carcinoma cells with antrocinol, a novel, dual-specificity, small-molecule inhibitor of the KRAS and ERK oncogenic signaling pathways
Authors:	徐嘉鴻 Chia-Hung Hsu, Pei?Wei Weng, Ming-Yao Chen, Chi-Tai Yeh, Syahru Agung Setiawan, Vijesh Kumar Yadav, Alexander T.H. Wu, David T.W. Tzeng, Jian-Xian Gong, Zhen Yang, Yew-Min Tzeng
Contributors:	醫學系急診學科
Keywords:	Keywords: Hepatocellular carcinoma;Antrocinol;Sorafenib;KRAS/AKT/ERK axis;Cancer stemness
Date:	2023-01
Issue Date:	2025-03-28 10:59:51 (UTC+8)
Abstract:	Abstract: Until recently, sorafenib has been the only treatment approved by the U.S. Food and Drug Administration for patients with advanced hepatocellular carcinoma (HCC). Some patients, however, exhibit resistance to this treatment and subsequently experience cancer progression, recurrence, or death. Therefore, identifying a new alternative treatment for patients with little or no response to sorafenib treatment is vital. In this study, we explored the therapeutic potential and underlying molecular mechanism of antrocinol ((3aS,4R,6aS,10aR)-4-(hydroxymethyl)-7,7-dimethyldecahydro-1H-naphtho[1,8a-c]furan-1-one) in patients with HCC. The results indicated that antrocinol was more therapeutically effective than antrocin, Stivarga, and sorafenib against HCC cell lines. Antrocinol also substantially suppressed the expression of KRAS-GTP, p-MEK1/2, p-ERK1/2, and p-AKT in the Huh7 cell line. Additionally, antrocinol-induced apoptosis in the Huh7 cell line, inhibited the formation of tumorspheres, and suppressed the expression of cancer stem cell markers CD133, KLF4, CD44, OCT4, SOX2, and c-Myc. Animal studies revealed that antrocinol alone considerably suppressed tumor growth in nonobese diabetic/severe combined immunodeficient mice inoculated with Huh7 tumorspheres. It also synergistically enhanced the anticancer effect of sorafenib, resulting in enhanced suppression of tumor growth (p?<?0.001) and tumorsphere formation (p?<?0.001). In tumor samples resected from mice treated with antrocinol alone or in combination with sorafenib, immunohistochemical analysis revealed an increase in BAX expression and a decrease in ERK and AKT protein expression. To the best of our knowledge, this is the first report of the anti-HCC activity of antrocinol. With its higher therapeutic efficacy than that of sorafenib, antrocinol is a candidate drug for patients with HCC who demonstrate little or no response to sorafenib treatment.
Relation:	Chemico-Biological Interactions, Volume 370, 2023, 110329
Description:	【112 新聘】臺北醫學大學教師升等專門著作職別：專任送審等級：助理教授著作送審
Data Type:	article
Appears in Collections:	[教師升等送審著作] 112 [急診學科] 期刊論文

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