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: Tung-Cheng Chang, Chi-Tai Yeh, Bamodu Oluwaseun Adebayo, Ying-Chin Lin, Li Deng, Yerra Koteswara Rao, Chun-Chih Huang, Wei-Hwa Lee, Alexander T H Wu, Michael Hsiao, Chih-Hsiung Wu, Liang-Shun Wang, Yew-Min Tzeng
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 288 Issue 2 Pg. 258-68 (Oct 15 2015) ISSN: 1096-0333 [Electronic] United States
• PMID: 26235807 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Cyclohexanones
• Organoplatinum Compounds
• 4-acetylantroquinonol B
• 4-Butyrolactone
• Leucovorin
• Fluorouracil

Topics

• 4-Butyrolactone (analogs & derivatives, pharmacology)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cyclohexanones (pharmacology)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Fluorouracil (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• HT29 Cells
• Humans
• Leucovorin (pharmacology)
• Mice, Inbred NOD
• Mice, SCID
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Organoplatinum Compounds (pharmacology)
• Phenotype
• Signal Transduction (drug effects)
• Spheroids, Cellular
• Time Factors
• Tumor Burden
• Xenograft Model Antitumor Assays