Collateral Sensitivity of sigma-2 Receptor ligands: Potentials in the Treatment of Multidrug Resistant Tumors

Abstract

  Tumors remain one of the main causes of human illnesses and death with MultiDrug Resistance (MDR) being the most severe limitation to the success of chemotherapy. MDR is mainly due to the overexpression of drug efflux transporters, such as P-glycoprotein (P-gp), but attempts to inhibit P-gp have not been clinically successful so far. Lately, some agents were found to be more effective against P-gp overexpressing cells, showing a property termed “collateral sensitivity” (CS). The molecular bases of CS are poorly understood and hypersensitivity to reactive oxygen species (ROS) is one of the hypotheses that accounts for it. We recently identified a few sigma-2 (s₂) receptors ligands endowed with CS, likely because of their interaction with P-gp. In fact, a number of CS agents are P-gp substrates: they are actively effluxed by P-gp, and it is believed that they activate a futile ATP cycle, increase oxidative phosphorylation leading to higher ROS production and oxidative stress. Therefore, we verified ROS involvement to study the CS properties of s₂ receptors ligands/P-gp substrates (F408 and siramesine) whose activity was measured in three parental and Pg-p-overexpressing cell line pairs. We also demonstrated the major consumption of ATP induced by these compounds in P-gp overexpressing vs the parental cells. We analyzed the effects of siramesine and F408 on mitochondrial respiratory chain (source of ROS and intracellular ATP). Siramesine and F408 decreased both the electron flux rate and the ATP levels, with MDR cells undergoing a much more pronounced decrease than parent cells. Therefore, we demonstrated depletion of mitochondrial ATP supply by siramesine and F408 as the mechanism by which these s₂ ligands likely induce CS. In conclusion, CS and s₂ ligands-mediated actions warrant further investigation as a way to face MDR.