Abstract
Abstract
The use of anti-cancer adjuvant therapy is rationalized by potentiating the efficacy, and/or protecting from major side effects of chemotherapeutics. Gemcitabine and 5-fluorouracil are important chemotherapeutic agents which are frequently used to treat cancers such as colorectal cancer. Colossolactone-G is a naturally occurring triterpenoid metabolite isolated from the fruiting body of Ganoderma colossum. Herein, we assessed the potential chemomodulatory effects of Colossolactone-G to 5-fluorouracil and gemcitabine against human colorectal cancer cells. After 72 h of exposure, colossolactone-G per se possesses cytotoxic effects against HCT116 and HT29 cells with IC50's of 15.9±3.6 µM and 90.5±1.7 µM, respectively. In addition, colossolactone-G improved the cytotoxic profile of gemcitabine against HCT116 cells reducing its IC50 from 0.28±0.1 µM to 19.41±3.1 nM with combination index indicative of synergism (CI-value = 0.154). Similarly, colossolactone-G enhanced the cytotoxicity of gemcitabine against HT29 cells reducing its IC50 from 6.2±1.1 µM to 0.6±0.3 µM with combination index indicative of synergism (CI-value = 0.219). Besides, colossolactone-G synergized the cytotoxic profile of 5-fluorouracil against HCT116 and HT29 cells decreasing its IC50's from 10.8±4.6 to 3.1±0.5 µM (CI-value = 0.302), and from 12.9±3.7 to 3.2±0.6 µM (CI-value = 0.426), respectively. By assessing cell cycle distribution after 24 h using DNA content flowcytometry, both gemcitabine and 5-fluorouracil induced moderate cell cycle arrest at S-phase which was increased by combination with colossolactone-G and was further extended to induce accumulation of cells at G0/G1-phase. Longer exposure (48 h) of cells to colossolactone-G alone induced antiproliferative effect and accumulation of cells at G0/G1-phase. Besides, the S-phase arrest induced by gemcitabine and 5-fluorouracil was further increased by combination with colossolactone-G for 48 h and was accompanied by reciprocal decrease in cells in G2/M-phase. Cell cycle arrest attributed to gemcitabine and 5-fluorouracil treatment resulted in increasing cells undergoing apoptosis as shown by annexin-V/FITC staining. Similarly, combination with colossolactone increased the percentage of cells undergoing apoptosis in both cell lines. In conclusion, colossolactone-G represents promising chemomodulatory compound of natural origin which improves the anti-colorectal cancer activity of gemcitabine and 5-fluorouracil in a cell cycle dependent manner. Detailed molecular assessment for the underlying mechanisms of colossolactone-G chemomodulatory activity is currently under investigation.
Citation Format: Rinad A. Aljohani, Gehan A. Hegazy, Aliaa A. Alamoudi, Ali M. El-Halawany, Riham S. Eldine, Ghada Agabnoor, Ahmed M. Al-Abd. Colossolactone-G enhances the anticancer properties of 5-fluorouracil and gemcitabine against colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5819.