CB2 and TRPV1 receptors mediate cannabinoid actions on MDR1 expression in multidrug resistant cells.
Cannabis 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. Here we examined the role of cannabinoid receptors and transient receptor potential vanilloid type 1 (TRPV(1)) receptors in the effects of plant-derived cannabinoids on MDR1 mRNA expression in MDR CEMVLB(100) cells which overexpress P-gp due to MDR1 gene amplification. We showed that both cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) (10 μM) transiently induced the MDR1 transcript in P-gp overexpressing cells at 4 but not 8 or 48 h 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 4 h that slowly diminished by 48 h. CEMVLB(100) cell lines were shown to express CB(2) and TRPV(1) receptors. Δ(9)-THC effects on MDR1 expression were mediated by CB(2) receptors. The effects of CBD were not mediated by either CB(2) or TRPV(1) receptors alone, however, required activation of both these receptors to modulate MDR1 mRNA expression. This is the first evidence that CB(2) and TRPV(1) receptors cooperate to modulate MDR1 expression.