Abstract 1751: Y15 and Pyridoxal 5′ Phosphate enhances the cytotoxic profile of Cisplatin and Paclitaxel in platinum resistant ovarian cancer cells

Abstract

Abstract Overexpression of the Tyrosine Kinase, Focal Adhesion Kinase (FAK) has been implicated in the development of resistance to front line agents, cisplatin and paclitaxel, in the treatment of ovarian cancer. Moreover vitamins such as Pyridoxal 5′ phosphate (PLP) has been shown to induce cytotoxicity in cancers. Therefore, the aim of this study was to assess the cytotoxic efficacy of FAK inhibition using 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15) and PLP combined with cisplatin and paclitaxel. Platinum resistant OVCAR-3 cells were treated with varying concentrations of Y15 (10μM, 15 μM, 30 μM, 100 μM), and PLP (0.25mM, 1mM, 2Mm). Cells were also treated with Y15 + PLP, Y15 + Cisplatin + Paclitaxel, PLP + cisplatin + paclitaxel and Cisplatin + paclitaxel for 24 hrs in triplicate and control cells with 2N HCl or media only. The cytotoxic profile of each treatment was assessed using the automated trypan blue assay and DNA fragmentation assay was performed to evaluate the mechanism of cell death. Dose dependent and statistically significant cytotoxicities were seen with Y15 and PLP compared to the controls with IC 50 values 80 μM (p <0.05) and 2 mM (p<0.05) respectively. The use of Y15 in combination with PLP showed enhanced cytotoxic efficacy in OVCAR-3 cell (p<0.0001). Similarly, Y15 significantly increased percentage cell death when combined with cisplatin + paclitaxel (62%, p<0.0001) in comparison to cisplatin + paclitaxel (35%). The use of PLP with cisplatin + paclitaxel also showed a greater cytotoxic profile of 55% (p<0.002). Cell death by apoptosis was not confirmed by DNA fragments in Y15 and PLP positive treatment groups. Y15 and PLP significantly enhances the cytotoxic profile of cisplatin, paclitaxel in resistant OVCAR-3 cells suggesting that targeting FAK activity through the inhibition of Y397 site and the use of PLP augments resistance to paclitaxel and cisplatin. However further studies are needed to determine the mechanistic pathway of Y15 and Pyridoxal 5′Phosphate induce cytotoxicity. Citation Format: Monique P. Reboe, Terry-ann Waite, Arkene S. Levy, Sivanesan Dhandayuthapani, Appu Rathinavelu. Y15 and Pyridoxal 5′ Phosphate enhances the cytotoxic profile of Cisplatin and Paclitaxel in platinum resistant ovarian cancer cells. [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 1751. doi:10.1158/1538-7445.AM2015-1751