4-Acetylantroquinonol B inhibits colorectal cancer tumorigenesis and suppresses cancer stem-like phenotype

• Published in: Toxicology and applied pharmacology Vol. 288; no. 2; pp. 258 - 268
• Main Authors: Chang, Tung-Cheng, Yeh, Chi-Tai, Adebayo, Bamodu Oluwaseun, Lin, Ying-Chin, Deng, Li, Rao, Yerra Koteswara, Huang, Chun-Chih, Lee, Wei-Hwa, Wu, Alexander T.H., Hsiao, Michael, Wu, Chih-Hsiung, Wang, Liang-Shun, Tzeng, Yew-Min
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2015
• Subjects: 4-Acetylantroquinonol B; 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - pharmacology; 60 APPLIED LIFE SCIENCES; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antrodia camphorata; Cancer progression; Cancer stem cells; CARCINOMAS; CELL PROLIFERATION; Cell Proliferation - drug effects; CHEMOTHERAPY; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cyclohexanones - pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fluorouracil - pharmacology; FLUOROURACILS; Gene Expression Regulation, Neoplastic - drug effects; HCT116 Cells; HT29 Cells; Humans; IN VIVO; INFLAMMATION; Leucovorin - pharmacology; MAINTENANCE; Mice, Inbred NOD; Mice, SCID; MUSHROOMS; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Organoplatinum Compounds - pharmacology; PHENOTYPE; PHOSPHOTRANSFERASES; RECEPTORS; Signal Transduction - drug effects; SIGNALS; Spheroids, Cellular; STEM CELLS; Time Factors; Tumor Burden; TUMOR CELLS; TYROSINE; Xenograft Model Antitumor Assays; Cancer progression; Chemotherapy; 4-Acetylantroquinonol B; Cancer stem cells; Antrodia camphorata; Colorectal cancer
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.07.025

4-Acetylantroquinonol B (4-AAQB), closely related to the better known antroquinonol, is a bioactive isolate of the mycelia of Antrodia camphorata, a Taiwanese mushroom with documented anti-inflammatory, hypoglycemic, vasorelaxative, and recently demonstrated, antiproliferative activity. Based on its traditional use, we hypothesized that 4-AAQB may play an active role in the suppression of cellular transformation, tumor aggression and progression, as well as chemoresistance in colorectal carcinoma (CRC). In this study, we investigated the antiproliferative role of 4-AAQB and its underlying molecular mechanism. We also compared its anticancer therapeutic potential with that of antroquinonol and the CRC combination chemotherapy of choice — folinic acid, fluorouracil and oxaliplatin (FOLFOX). Our results showed that 4-AAQB was most effective in inhibiting tumor proliferation, suppressing tumor growth and attenuating stemness-related chemoresistance. 4-AAQB negatively regulates vital oncogenic and stem cell maintenance signal transduction pathways, including the Lgr5/Wnt/β-catenin, JAK–STAT, and non-transmembrane receptor tyrosine kinase signaling pathways, as well as inducing a dose-dependent downregulation of ALDH and other stemness related factors. These results were validated in vivo, with animal studies showing 4-AAQB possessed comparable tumor-shrinking ability as FOLFOX and potentiates ability of the later to reduce tumor size. Thus, 4-AAQB, a novel small molecule, projects as a potent therapeutic agent for monotherapy or as a component of standard combination chemotherapy. [Display omitted] •4-Acetylantroquinonol B (4-AAQB) suppressed tumor cell proliferation.•4-AAQB regulates oncogenic and stem cell maintenance signal pathways.•4-AAQB negatively regulates Lgr5/Wnt/β-catenin and JAK–STAT pathways.•4-AAQB reduced ALDH and other stemness related factor expression.•In vivo, 4-AAQB has comparable tumor-shrinking ability as FOLFOX.