Induction of apoptosis-like cell death by pentamidine and doxorubicin through differential inhibition of topoisomerase II in arsenite-resistant L. donovani

Abstract

The current study has been undertaken to investigate the sensitivity of the topoisomerase II (topo II) of wild type (Ld-Wt) and arsenite-resistant (Ld-As20) L. donovani to an anti-leishmanial agent pentamidine and an anti-cancer drug doxorubicin. We demonstrate that the cross resistance to pentamidine and doxorubicin in Ld-As20, was in part implicated through differential inhibition of topo II in Ld-Wt and Ld-As20. Further, the treatment of promastigotes at drug concentrations inhibiting 50% of topo II activity inflicted a regulated cell death sharing several apoptotic features like externalization of phosphatidylserine, loss of mitochondrial membrane potential, cytochrome C release into the cytosol, activation of cellular proteases and DNA fragmentation. The cytotoxic potential of pentamidine and doxorubicin in L. donovani has been shown to be mediated through topoisomerase II inhibition and results in inciting programmed cell death process.