Abstract
Abstract Background: Chemoresistance to 5-Fluorouracil (5-FU) is a common clinical problem during the treatment of colorectal cancer (CRC) and its pathogenesis includes hyperactivation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) oncogenic pathway that induces aerobic glycolysis. Although both calcitriol and metformin ameliorated the tumoricidal actions of 5-FU, there is no report on the potential anti-cancer effects of 5-FU, calcitriol, and metformin triple therapy. Objectives: This study aimed to measure the chemotherapeutic effects of 5-FU, calcitriol, and/or metformin single, dual, and triple treatments against CRC in vitro. Materials and methods: The HT29, SW480 and SW620 colon cancer cell lines were treated for 12 hours with 5-FU (50 µM), calcitriol (25 µM), and/or metformin (39.8 mM) single/dual/triple protocols followed by measuring cell cycle and cell apoptosis by flow cytometer. We also measured the gene and protein expression of cell cycle and apoptosis regulatory molecules alongside the PI3K/Akt/PTEN/mTOR network. Results: All therapies induced HT29 arrest at the S-phase of cell cycle, with calcitriol/metformin and 5-FU/calcitriol/metformin regimens most prominent (1.7-fold for both) relative to untreated cells. Alternatively, all therapies equally induced G1-phase arrest in the SW480 cells (~1.5-fold), whereas metformin-alone showed maximal numbers of SW620 cells in the G0/G1-phase (1.6-fold). 5-FU/metformin co-therapy also showed the highest numbers of apoptotic HT29 (11%) and SW480 (13%) cells, whilst 5-FU/calcitriol/metformin displayed the lowest percentage (81%) of viable SW620 cells. Triple therapy also revealed maximal downregulations of markers of cell cycle induction (CCND1/CCND3), cell survival (BCL2) and the PI3K/Akt/mTOR pathway, which coincided with highest expression of PTEN, cell cycle inhibitors (p21/p27), and pro-apoptotic (BAX/Cytochrome-C/Caspase-3) molecules in all three cell lines. Conclusions: The anti-cancer effects of metformin monotherapy were greater than calcitriol, whilst the 5-FU/metformin approach was better relative to the other dual therapies. However, the triple therapy protocol revealed the best tumoricidal actions related to cell cycle arrest and apoptosis in all cell lines, possibly by enhanced regulation of the PI3K/PTEN/Akt/mTOR pathway. Citation Format: Mohammed A. Baghdadi, Jawwad Ahmad, Shakir Idris, Mai Alhadrami, Riyad Almaimani, Mohammed Aslam, Bassem Refaat. Exploring the anti-cancer activities of 5-Fluorouracil, metformin, and calcitriol single, dual, and triple therapies against colon cancer cells in vitro: The role of PI3K/Akt/mTOR pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5803.
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