Abstract 5557: Chemotherapeutic and chemomodulatory effects of naturally occurring O-naphthoquinone and related coumarins against solid tumor cells in-vitro
Authors: Baghdadi Mohammed A. , Al-Abbasi Fahad A. , El-Halawany Ali M. , Al-Abd Ahmed M. 
Published: August 2015

Abstract
Napthoquinones are naturally occurring compounds with potential anticancer activity. In the current study a group of O-naphthoquinone compounds (mansonone-G, mansonone-N, mansonone-O and mansonone-S) and their structurally related coumarins (mansorin-A, mansorin-B, mansorin-C and mansorin-D) were isolated from the trunk of Mansonia Gagei family Sterculariaceae. Isolated compounds were examined for their potential anticancer activity in breast (MCF-7), cervix (HeLa), colorectal (CaCo-2) and liver (HepG2) cancer cells. Cytotoxicity of the isolated compounds was assessed in the aforementioned cell lines using SRB assay after 72 h of exposure and fitted using Emax model. Amongst naphthoquinones, mansonone-O showed the best cytotoxic profile in all cell lines under investigation with IC50 range from 0.74 to 36 μM; and R-fraction less than 5.7%. On the other hand, all coumarin compounds showed potentially low IC50 (from 1.0 to 38.7 μM) in all tested cell lines. However, the R-fraction reached as high as 90.5% in some cell lines (MCF-7). The effect of O-naphthoquinones and their related coumarins against P-gp efflux pump was tested and compared to verapamil using doxorubicin as P-gp probe. Mansonone-O, mansorin-C and mansorin-D inhibited the efflux activity of P-gp pump by 158.1%, 250.5% and 115.4%, respectively compared to 255.1% by verapamil. Accordingly, equitoxic combination of mansonone-O with paclitaxel against colorectal cancer cells was further investigated using Chou & Talaly equation. The IC50 of paclitaxel was significantly reduced after combination with mansonone-O compared to its single paclitaxel treatment (5.14 nM and 24.9 nM, respectively). The combination of paclitaxel with mansonone-O was synergistic in nature with calculated combination index of 0.33. Furthermore, cell cycle analysis was studied after combination of mansonone-O with paclitaxel. Combination of mansonone-O with paclitaxel significantly increased the cell population in G2/M phase (from 4.2±0.5% to 11.2±1.2%) with reciprocal decrease in the non-proliferating cell fraction (G0/G1) from 73.5±1.7% to 66.8±1.6%. In conclusion, mansonone-O (naturally occurring naphthoquinone) synergizes the anticancer effect of paclitaxel. This synergism might be partly attributed to interfering with the efflux activity of P-gp pump and/or interfering with cell cycle progression. Further mechanistic studies for the proposed intracellular targets of mansonone-O and related compounds is strongly recommended.
Citation Format: Mohammed A. Baghdadi, Fahad A. Al-Abbasi, Ali M. El-Halawany, Ahmed M. Al-Abd. Chemotherapeutic and chemomodulatory effects of naturally occurring O-naphthoquinone and related coumarins against solid tumor cells in-vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5557. doi:10.1158/1538-7445.AM2015-5557