title: 4-Acetylantroquinonol B inhibits colorectal cancer tumorigenesis and suppresses cancer stem-like phenotype.
abstract: 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.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
authors.forename: Tung-Cheng
authors.initials: TC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan; Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
authors.forename: Bamodu Oluwaseun
authors.initials: BO
authors.lastname: Adebayo
authors.affiliation: Department of Family Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ying-Chin
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Beijing Bioprocess Key Laboratory, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China; Amoy-BUCT Industrial Bio-technovation Institute, Amoy 361022, China.
authors.forename: Li
authors.initials: L
authors.lastname: Deng
authors.affiliation: Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung 41349, Taiwan.
authors.forename: Yerra Koteswara
authors.initials: YK
authors.lastname: Rao
authors.affiliation: Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung 41349, Taiwan.
authors.forename: Chun-Chih
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Pathology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
authors.forename: Wei-Hwa
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Alexander T H
authors.initials: AT
authors.lastname: Wu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan; Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan; Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan. Electronic address: wangls72269@yahoo.com.tw.
authors.forename: Liang-Shun
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung 41349, Taiwan. Electronic address: ymtzeng@cyut.edu.tw.
authors.forename: Yew-Min
authors.initials: YM
authors.lastname: Tzeng
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003512:Cyclohexanones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D013997:Time Factors; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003512:Cyclohexanones; D009944:Organoplatinum Compounds; C555021:4-acetylantroquinonol B; D015107:4-Butyrolactone; D002955:Leucovorin; D005472:Fluorouracil
keywords: 4-Acetylantroquinonol B; Antrodia camphorata; Cancer progression; Cancer stem cells; Chemotherapy; Colorectal cancer