Enhanced sensitivity of human ovarian carcinoma cell lines A2780 and A2780/CP to the combination of cisplatin and synthetic isothiocyanate ethyl 4-isothiocyanatobutanoate

Naturally occurring and synthetic isothiocyanates (ITCs) are known as chemopreventive agents. The present study shows a new synthetic ITC derivate ethyl 4-isothiocyanatobutanoate (E-4IB) as an effective modulator of cellular proliferation and inducer of apoptosis with potential utility as an anticancer drug, as well as a sensitizer to routinely used chemotherapeutic agent cisplatin (cis-Pt). Evaluation of the growth inhibitory effects of E-41B in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant variant A2780/CP using MTT-test and its apoptosis-inducing properties by flow cytometry was performed. Effect of E-41B was assessed both alone and in paired combination with cisplatin. Combination index (CI) values from Calcusyn software were used to characterize the interactions as synergistic, additive, or antagonistic. Significant synergistic effect in growth inhibition of E-41B (0.5-5 mu M) with cis-Pt (2.5-10 mu M) on A2780 parental cell line (CI from 0.39 to 0.75) was also observed on A2780/CP resistant subline, although to a lesser extent (CI from 0.43 to 0.86) for cis-Pt concentrations 5-25 mu M and the same concentrations of E-4IB. Synergy in growth inhibition correlated with the potential of E-41B to stimulate apoptosis induced by cis-Pt (from 9.5% to 24.7% at 24 hours) while E-41B alone induced 3.6% of apoptotic cells in A2780 cell line. We conclude that E-41B may be worth of further studies assessing its value in the ovarian carcinoma treatment, in combination with the other chemotherapeutic agents.