Overcoming multidrug resistance (MDR) in cancer in vitro and in vivo by a quinoline derivative

Abstract

Multidrug resistance (MDR) mediated by the over expression of drug efflux protein P-glycoprotein (P-gp) is one of the major impediments to successful treatment of cancer. P-gp acts as an energy-dependent drug efflux pump and reduces the intracellular concentration of structurally unrelated drugs inside the cells. Therefore, there is an urgent need for development of new compound that are less toxic and effective against drug resistance in cancer. Preclinical studies have shown that quinoline derivatives possess anticancer activities. Here, we report the antitumor potential of quinoline derivative, 2-(2-Methyl-quinolin-4ylamino)-N-phenyl acetamide (S4). To evaluate the cytotoxic potential of S4, we used four different cell lines (Hela, HCT-116, CCRF-CEM, and CEM/ADR 5000) in vitro, and showed that S4 kills doxorubicin resistant T lymphoblastic leukemia cell, CEM/ADR 5000 in a concentration dependent manner while others remains unaffected. Moreover, S4 induces apoptosis in CEM/ADR 5000 cells through generation reactive oxygen species (ROS). This is substantiated by the fact that the antioxidant N-acetyle-cysteine (NAC) completely blocks ROS generation and, subsequently, abrogates S4 induced apoptosis. Furthermore, in vivo treatment with S4 significantly increases the life span of swiss albino mice bearing sensitive and doxorubicin resistant subline of Ehrlich ascites carcinoma. In addition, intraperitoneal application of S4 in mice does not show any systemic toxicity at concentrations that in preliminary trials in a mice Ehrlich ascites carcinoma model. Therefore, present report provides evidence that S4, a quinoline derivative, may be a promising new therapeutic agent against drug resistant cancers.