Abstract LB-073: Mansonone-G is more potent antiproliferative against liver cancer cells than its coumarin derivative (mansorin-A) despite their antagonistic interaction with 5-fluorouracil
Authors: Hanadi G. Aljohani, Gehan A. Hegazy, Aliaa A. Alamoudi, Ghada M. Agabnoor, Ali M. El-Halawany, Ahmed M. Al-Abd
Journal: Cancer Research (2018)

Abstract O-Napthoquinones and their structurally related coumarins are naturally occurring compounds with potential anticancer properties. In the current work mansonone-G and its coumarin derivative, mansorin-A were isolated from the trunk of Mansonia Gagei family Sterculariaceae and evaluated for potential solo anticancer effects and/or chemomodulatory properties to 5-fluorouracil (5-FU) against liver cancer cells (HepG2 and Huh-7). Mansonone-G exerted moderate cytotoxic properties against both HepG2 and Huh-7 cells with IC50's of 36.3±2.6 µM and 25.9±2.7 µM; and resistance fraction (R-value) of 4.7±0.1% and 3.4±0.4%, respectively. However, mansorin-A exerted weaker cytotoxic profile against the same cell lines (HepG2 and Huh-7) with IC50's of 24.6±1.7 µM and 29.5±5.8 µM, respectively; and R-values were higher than 50% in both cell lines. Surprisingly, mansonone-G attenuated the potency of 5-FU against both cell lines under investigations (HepG2 and Huh-7) and increased its IC50's from 0.8±0.2 to 36.5±7.2 µM and from 2.6±0.2 to 10.1±2.1 µM, respectively. Interestingly, equitoxic combination of mansonone-G abolished the R-fractions of both cell lines (HepG2 and Huh-7) to 5-FU from 39.4±2.7% and 53.2±1.7%, respectively to less than 5% in both cell lines. Similarly but to lesser extent, mansorin-A increased the IC50's of 5-FU against HepG2 and Huh-7 cells from 0.8±0.2 to 56.0±12.7 µM and from 2.6±0.2 to 7.4±3.9 µM, respectively. Similarly, equitoxic combination of mansorin-A abolished the R-fractions of both cell lines to 5-FU to less than 5%. To confirm these apparent antagonism interactions between mansonone-G or mansorin-A with 5-FU, apoptosis/necrosis analysis for single and combination treatments was undertaken using annexin-V/FITC staining coupled with flowcytometry. Mansorin-A significantly decreased apoptotic cell death attributed to treatment with 5-FU in both HepG2 and Huh-7 cell lines. However, mansonone-G significantly increased apoptosis induced by 5-FU in both cell lines. In addition to apoptosis, autophagic cell death was assessed using acridine orange staining coupled with flowcytometry. Mansorin-A did not influence autophagic cell death; 5-FU increased cells undergoing autophagy; and mansonone-G decreased cells undergoing autophagy. Mansorin-A combination decreased 5-FU induced autophagic cell death. On the other hand, combination of mansonone-G with 5-FU resulted in decreased autophagic cell death. By studying the influence of treatments under investigation to cell cycle distribution using DNA content flowcytometry, both mansonone-G and mansorin-A induced significant cell cycle accumulation in G0/G1-phase. This antiproliferative effect of mansonone-G and mansorin-A prohibit cell progression to S-phase and accordingly might result in desensitizing cells to the S-phase selective cytotoxicity of 5-FU. In conclusion, despite the potential antiproliferative effects of mansonone-G and mansorin-A against liver cancer cells, they antagonize the cytotoxic effects of the S-phase specific agents such as 5-FU. In addition, this antagonism might be partly attributed to conflicting autophagic effects of mansonone-G/mansorin-A and 5-FU. Citation Format: Hanadi G. Aljohani, Gehan A. Hegazy, Aliaa A. Alamoudi, Ghada M. Agabnoor, Ali M. El-Halawany, Ahmed M. Al-Abd. Mansonone-G is more potent antiproliferative against liver cancer cells than its coumarin derivative (mansorin-A) despite their antagonistic interaction with 5-fluorouracil [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 LB-073.