| Summary: | 5-Fluorouracil (5-FU) regimen remains the backbone of the first-line agent to treat colon cancer, but often these patients develop resistance. Cancer stem cells (CSC’s) are considered as one of the key contributors in the development of drug resistance and tumor recurrence. We aimed to provide preclinical evidence for <i>Antrodia cinnamomea</i> (<i>AC</i>), as a potential in suppressing colon cancer CSC’s to overcome 5-FU drug-resistant. In-vitro assays including cell viability, colony formation, <i>AC</i> + 5-FU drug combination index and tumor sphere generation were applied to determine the inhibitory effect of <i>AC</i>. Mouse xenograft models also incorporated to evaluate in vivo effect of <i>AC</i>. <i>AC</i> treatment significantly inhibited the proliferation, colony formation and tumor sphere generation. <i>AC</i> also inhibited the expression of oncogenic markers (NF-κB, and C-myc), EMT/metastasis markers (vimentin and MMP3) and stemness associated markers (β-catenin, SOX-2 and Nanog). Sequential treatment of <i>AC</i> and 5-FU synergized and reduces colon cancer viability both in vivo and in vitro. Mechanistically, <i>AC</i> mediated anti-tumor effect was associated with an increased level of tumor suppressor microRNAs especially, miR142-3p. <i>AC</i> can be a potent synergistic adjuvant, down-regulates cancer stemness genes and enhances the antitumor ability of 5-FU by stimulating apoptosis-associated genes, suppressing inflammation and metastasis genes through miR142-3p in colon cancer.
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