Abstract 305: Combination analysis for the potential chemomodulatory effects of mansorin-A and its naphthoquinone derivative (mansonone-G) to 5-fluorouracil against liver cancer cells

Abstract

Abstract Mansorin-A and its naphthoquinone derivative, mansonone-G are naturally occurring compounds isolated from the trunk of Mansonia gagei, family Sterculariaceae. In a previous work, they showed potential anticancer effects besides their antioxidant properties. Herein, we investigated their potential chemomodulatory effects to 5-fluorouracil (5FU) against two liver cancer cell lines (Huh7 and HepG2). Despite the significant cell killing effect of 5FU to Huh7 and HepG2 cells (IC50’s of 2.6±0.2 µM and 0.82 ± 0.2 µM, respectively), the resistance fractions of both cell lines were considerably high (53.2±1.7% and 39.4±2.7%, respectively). Mansorin-A and mansonone-G induced moderate cytotoxicity against both liver cancer cell lines with IC50’s ranging from 25.8±3.2 µM to 36.3±2.7 µM. In Huh7, mansorin-A and mansonone-G synergized cell killing effect of 5FU and decreased its IC50’s to 0.9±0.1 and 1.0±2.1 µM, respectively. On the other hand, mansorin-A and mansonone-G showed apparent antagonism by combination with 5FU (CI values of 6.2 and 9.4, respectively) against HepG2 cells. However, both compounds significantly abolished the resistant fraction of HepG2 to 5FU (3.3±0.3% and 8.4 ± 2.6%, respectively). Further investigation showed that mansonone-G alone showed antiproliferative effect and arrested cells in G0/G1-phase. Both mansorin-A and mansonone-G enhanced 5FU induced cell cycle arrest at G0/G1-phase with reciprocal decrease in cells entering S-phase and G2/M-phase. In addition, apoptosis due to 5FU treatment alone and in combination with mansorin-A and mansonone-G was assessed using annexin-V/FITC staining coupled with flowcytometry. Yet, both mansorin-A and mansonone-G enhanced 5FU induced apoptotic effect against liver cancer cells. Mansonone-G alone induced significant apoptosis in both HepG2 and Huh7 cells. Besides apoptosis, autophagy induction properties of mansorin-A and mansonone-G were assessed using flowcytometry after acridine orange staining. Mansonone-G aborted autophagy in both HepG2 and Huh7 cell lines and indirectly forced liver cancer cells to undergo apoptotic cell death. On the other hand, both mansorin-A and mansonone-G significantly induced the production of reactive oxygen species within both HepG2 and Huh-7 cells which might directly induce apoptosis in both cell lines. In conclusion, mansonone-G and to a lesser extent mansorin-A, potentiated the anticancer properties of 5FU against liver cancer cells via potentiating its cell cycle arrest and potentiating its apoptotic influence due to ROS production. Citation Format: Hanadi G. Aljohani, Gehan A. Hegazy, Ali M. El-Halawany, Aliaa A. Alamoudi, Ghada M.A. Agabnoor, Ahmed M. Al-Abd. Combination analysis for the potential chemomodulatory effects of mansorin-A and its naphthoquinone derivative (mansonone-G) to 5-fluorouracil against liver cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 305.