Abstract
DLBCL is an aggressive disease and the most common type of non-Hodgkin lymphoma among adults. Endocannabinoids have been shown to produce anti-proliferative and pro-apoptotic actions in a broad spectrum of tumors. FAAH is the primary enzyme responsible for regulating levels of endocannabinoids. Here we explore the role of FAAH inhibition in DLBCL.
Western blot analysis was used to probe for FAAH expression in the human DLBCL cell lines, U2392 and Ly-7. The apoptotic effect of an FAAH inhibitor (URB 597) was tested. Next, DLBCL was co-treated with URB 597 and an endocannabinoid (AEA) to simulate endocannabinoid accumulation in cancer tissues. Cellular apoptosis rates were measured by Annexin V and Caspase 3/7 staining and flow cytometry.
High levels of FAAH were observed in both DLBCL cell lines. AEA alone induced significant apoptosis over vehicle control in a dose dependent manner. The greatest change was observed at 30 μm AEA treatment, which resulted in a 9.8 fold increase in apoptosis rate (p<0.001). Together with URB597, AEA increased DLBCL death dramatically in a supra-additive manner. The most significant change was observed at co-treatment levels of 10 μM URB597 and 30 μM AEA, which resulted in a 16.8 fold increase (p<0.001) in apoptosis rate compared to vehicle control.
FAAH inhibition is a promising approach to induce cell death in DLBCL tumors. Studies are in progress to test the in vivo efficacy of FAAH inhibition and the underlying pathogenic mechanisms.