Collateral sensitivity as a strategy against cancer multidrug resistance

Abstract

While chemotherapy remains the most effective treatment for disseminated tumors, acquired or intrinsic drug resistance accounts for approximately 90% of treatment failure. Multidrug resistance (MDR), the simultaneous resistance to drugs that differ both structurally and mechanistically, often results from drug efflux pumps in the cell membrane that reduce intracellular drug levels to less than therapeutic concentrations. Expression of the MDR transporter P-glycoprotein (P-gp, MDR1, ABCB1) has been shown to correlate with overall poor chemotherapy response and prognosis. This review will focus on collateral sensitivity (CS), the ability of compounds to kill MDR cells selectively over the parental cells from which they were derived. Insights into CS may offer an alternative strategy for the clinical resolution of MDR, as highly selective and potent CS agents may lead to drugs that are effective at MDR cell killing and tumor resensitization. Four main mechanistic hypotheses for CS will be reviewed, followed by a discussion on quantitative and experimental evaluation of CS.

Fig. 1

Scheme demonstrating how chemotherapeutics selectively kill the sensitive (black) sub-population of tumor cells from among a heterogenous malignant population. During the recovery phase multidrug resistant (striped) tumor cells re-populate, and repeated chemotherapeutic cycles result in an intractable multidrug resistant tumor. Treatment with CS agents can kill P-gp-expressing cells and/or reduce P-gp expression, potentially priming tumor cells for treatment with chemotherapeutics.

Fig. 2

Scheme showing how substrates that stimulate P-gp ATPase activity and redox cycling agents can contribute to ROS production within cells. Substrates (left): The addition of a non-toxic substrate and subsequent futile cycling of the transporter consumes ATP, and its repletion results in ROS generation, while parental lines lacking P-gp are not exposed to ROS. The differential ROS generation results in preferential killing of MDR cells. Metal-mediated redox: Small molecule chelators that complex with endogenous iron or copper are known to allow redox-cycling and the resultant ROS generation would induce CS as put forward for organic redox cycling molecules. Increased levels of ROS converts glutathione (GSH) into its oxidized form glutathione disulfide (GSSH). Increased levels of GSSH is considered an indicator of cellular stress.