Antrodia cinnamomea Enhances Chemo-Sensitivity of 5-FU and Suppresses Colon Tumorigenesis and Cancer Stemness via Up-Regulation of Tumor Suppressor miR-142-3p

Abstract

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 Antrodia cinnamomea (AC), as a potential in suppressing colon cancer CSC’s to overcome 5-FU drug-resistant. In-vitro assays including cell viability, colony formation, AC + 5-FU drug combination index and tumor sphere generation were applied to determine the inhibitory effect of AC. Mouse xenograft models also incorporated to evaluate in vivo effect of AC. AC treatment significantly inhibited the proliferation, colony formation and tumor sphere generation. AC 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 AC and 5-FU synergized and reduces colon cancer viability both in vivo and in vitro. Mechanistically, AC mediated anti-tumor effect was associated with an increased level of tumor suppressor microRNAs especially, miR142-3p. AC 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.

Puerarin Ameliorates 5-Fluorouracil–Induced Intestinal Mucositis in Mice by Inhibiting JAKs

“…As a first-line chemotherapeutic agent, 5-fluorouracil (5-FU) is widely used in cancer treatments (Huang et al, 2019). The most common adverse reaction in the course of chemotherapy, 5-FU-induced intestinal mucositis is characterized by diffuse intestinal mucosal barrier disruption, and patients present with diarrhea, weight loss, and malnutrition as the main symptoms (Gan et al, 2020).…”

Patient-Derived Tumor Chemosensitization of GKB202, an Antrodia Cinnamomea Mycelium-Derived Bioactive Compound

“…A purified derivative of maleic and succinic acid, YMGKI-1, was previously discovered in those ACM ethanolic extracts which have shown inhibition in the stemness of head and neck cancer initiating cells both in vitro and in vivo [ 12 ]. Despite the increasing evidence that AC has the capability to diminish the stemness of cancer initiating cells through modulating tumor miRNA expressions [ 13 , 14 , 15 ], there are still great challenges to translate in vivo findings into current human clinical trials endpoints [ 16 ].…”

Portrait of Cancer Stem Cells on Colorectal Cancer: Molecular Biomarkers, Signaling Pathways and miRNAome

“…The treatment with Antrodia cinnamomea (AC) decreases the number, cell viability, inhibits self-renewal capacity, and induces apoptosis of colon tumor spheres, due to the downregulation of cancer-associated stemness marker such as β-catenin, SOX2, NANOG, and of EMT-related genes such as vimentin and MMP3, and upregulation of miR142-3p. AC combined with 5-FU increase the sensitivity of CRC cells to chemotherapeutic drugs and synergistically suppress the neoplastic cell viability by stimulating the expression of apoptosis-related genes and suppressing inflammation and metastasis-related genes through miR142-3p [ 198 ].…”