CB2 and TRPV1 receptors mediate cannabinoid actions on MDR1 expression in multidrug resistant cells

Abstract

BackgroundCannabis is the most widely used illicit drug in the world that is often used by cancer patients in combination with conventional anticancer drugs. Multidrug resistance (MDR) is a major obstacle in the treatment of cancer. An extensively characterized mechanism of MDR involves overexpression of P-glycoprotein (P-gp), which reduces the cellular accumulation of cytotoxic drugs in tumor cells. MethodsHere we examined the role of cannabinoid receptors and transient receptor potential vanilloid type 1 (TRPV1) receptors in the effects of plant-derived cannabinoids on MDR1 mRNA expression in MDR CEM/VLB100 cells which overexpress P-gp due to MDR1 gene amplification. ResultsWe showed that both cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) (10μM) transiently induced the MDR1 transcript in P-gp overexpressing cells at 4 but not 8 or 48h incubation durations. CBD and THC also concomitantly increased P-gp activity as measured by reduced accumulation of the P-gp substrate Rhodamine 123 in these cells with a maximal inhibitory effect observed at 4h that slowly diminished by 48h. CEM/VLB100 cell lines were shown to express CB2 and TRPV1 receptors. Δ9-THC effects on MDR1 expression were mediated by CB2 receptors. The effects of CBD were not mediated by either CB2 or TRPV1 receptors alone, however, required activation of both these receptors to modulate MDR1 mRNA expression. ConclusionThis is the first evidence that CB2 and TRPV1 receptors cooperate to modulate MDR1 expression.