Abstract
Dysregulation of cellular proliferation and evasion of apoptosis are key contributors to colon cancer (CoCa) development. Chemotherapeutic agents such as 5-Fluorouracil (5FU) and Oxaliplatin (OxT) which are frequently offered to treat CoCa are known to target cells in S and G2 phase of cell cycle. Cancer cells often overcome the effects of 5FU and OxT by deregulating cell cycle in response to these drugs. Therefore, to improve the cytotoxic effect of these chemotherapeutic agents it is important to keep CoCa cells in S and G2 phase. Hence, understanding the molecular mechanisms involved in CoCa cell-cycle progression and chemotherapeutic response could provide strategies for developing effective treatment options. Hence, in this study, we determined the effect of natural agent “Emodin” on CoCa cell-cycle regulation and its ability to increase the efficacy of 5FU and OxT by cell cycle regulation. The effects of Emodin, 5FU, and OxT as a single agent or in combination on CoCa (DLD-1, COLO-201, HCT116 p53WT, and HCT116 p53-/-) cell viability were determined by MTT assays. Combination index of Emodin, 5FU, and OxT were evaluated using Calcusyn. Emodin-induced changes in molecules involved in cell-cycle regulation and proliferation were analyzed via RT-PCR and confirmed by western blot (WB) analysis. Cell-cycle distribution with Emodin treatment alone and in combination with 5FU and OxT were assessed via flow cytometry and WB. Collectively, our data shows that Emodin alone was able to decrease cell survival and induced apoptosis in CoCa cells. Furthermore, cytotoxic ability of 5FU and OxT was increased when combined with Emodin as compared to when these chemotherapeutic drugs were given as single agents Emodin-induced cell-cycle regulation resulted in increased expression of tumor suppressor genes such as p21, p27 and p53, modulated cyclin/cyclin-dependent kinase expression, and induced cell-cycle arrest. Emodin also negatively impacted several signaling pathways associated with cell growth and differentiation. Overall, this study demonstrates that Emodin could be a promising adjuvant to either 5-Fluorouracil or Oxaliplatin in the treatment of CoCa.
Citation Format: Ian T. Saunders, Dexter Ezeagwu, Naresh Kumar, Hina Mir, Shailesh Singh. Emodin enhances efficacy of Oxaliplatin and 5 Fluorouracil in colon cancer by promoting cell cycle arrest [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2428.
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