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

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

doi:10.1016/j.cbi.2022.110329

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

Chem Biol Interact. 2023 Jan 25:370:110329. doi: 10.1016/j.cbi.2022.110329. Epub 2022 Dec 22.

Authors

Affiliations

¹ Department of Emergency Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan; Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei City, 11031, Taiwan; Department of Emergency Medicine, School of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
² Department of Orthopaedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Department of Orthopaedics, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 23561, Taiwan; Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, 11031, Taiwan.
³ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City, 23561, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
⁴ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City, 23561, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung, 95092, Taiwan.
⁵ International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
⁶ Ph.D. Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
⁷ School of Life Sciences, The Chinese University of Hong Kong, 999077, Hong Kong Special Administrative Region of China; Lifebit, London, EC2A 2AP, UK.
⁸ Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; Shenzhen Bay Laboratory, Shenzhen, 518055, China.
⁹ Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; State Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education and Beijing National Laboratory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China; Shenzhen Bay Laboratory, Shenzhen, 518055, China. Electronic address: zyang@pku.edu.cn.
¹⁰ Department of Applied Science, National Taitung University, Taitung, 95092, Taiwan; Department of Applied Chemistry, Chaoyang University of Technology, Taichung, 41349, Taiwan. Electronic address: ymtzeng@nttu.edu.tw.

PMID: 36565974
DOI: 10.1016/j.cbi.2022.110329

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.

Keywords: Antrocinol; Cancer stemness; Hepatocellular carcinoma; KRAS/AKT/ERK axis; Sorafenib.

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Apoptosis
Carcinoma, Hepatocellular* / pathology
Cell Line, Tumor
Liver Neoplasms* / pathology
MAP Kinase Signaling System
Mice
Niacinamide / pharmacology
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins p21(ras)
Signal Transduction
Sorafenib / pharmacology
Sorafenib / therapeutic use

Substances

Sorafenib
Proto-Oncogene Proteins p21(ras)
Antineoplastic Agents
Proto-Oncogene Proteins c-akt
Niacinamide