Cannabinoid derivatives exert a potent anti-myeloma activity bothin vitroandin vivo

Abstract

Although hematopoietic and immune system show high levels of the cannabinoid receptor CB2, the potential effect of cannabinoids on hematologic malignancies has been poorly determined. Here we have investigated their anti-tumor effect in multiple myeloma (MM). We demonstrate that cannabinoids induce a selective apoptosis in MM cell lines and in primary plasma cells of MM patients, while sparing normal cells from healthy donors, including hematopoietic stem cells. This effect was mediated by caspase activation, mainly caspase-2, and was partially prevented by a pan-caspase inhibitor. Their pro-apoptotic effect was correlated with an increased expression of Bax and Bak, a decrease of Bcl-xL and Mcl-1, a biphasic response of Akt/PKB and an increase in the levels of ceramide in MM cells. Inhibition of ceramide synthesis partially prevented apoptosis, indicating that these sphingolipids play a key role in the pro-apoptotic effect of cannabinoids in MM cells. Remarkably, blockage of the CB2 receptor also inhibited cannabinoid-induced apoptosis. Cannabinoid derivative WIN-55 enhanced the anti-myeloma activity of dexamethasone and melphalan overcoming resistance to melphalan in vitro. Finally, administration of cannabinoid WIN-55 to plasmacytoma-bearing mice significantly suppressed tumor growth in vivo. Together, our data suggest that cannabinoids may be considered as potential therapeutic agents in the treatment of MM.

Disease-Specific Derangement of Circulating Endocannabinoids and N-Acylethanolamines in Myeloproliferative Neoplasms

“…Recently, interest in the EC system emerged for another hematological malignancy, multiple myeloma (MM). Indeed, it was shown that plasma cells expressed high levels of CB2 and that cannabinoid derivatives selectively induced apoptosis in MM cell lines and primary plasma cells from MM patients [23], similarly to what previously reported for AML [29]. Hence, the EC system in these malignancies might represent a potential target for therapeutic exploitation.…”

“…Interestingly, ECs have been recently found to modulate hematopoiesis, including megakaryocyte maturation, thrombopoiesis, and platelet aggregation, as well as chemokine release and migration of immunocompetent cells [15,[20][21][22]. Importantly, blood cells and platelets act as sources of ECs, whereas various hematopoietic cell subsets, particularly B-cells, display high levels of CB2 [23]. In addition, ECs released by platelets are involved in thrombogenic processes [24].…”

Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

“…They demonstrated that THC (tetrahydrocannabinol) caused an increase in ceramide levels through de novo synthesis, which led to apoptosis in C6 glioma cells. This increase of ceramide levels through THC or other cannabinoids was also shown in prostate and colon cancer cells, as well as mantle cell lymphoma (MCL) and multiple myeloma (Barbado et al, 2017; Cianchi et al, 2008; Gustafsson, Christensson, Sander, & Flygare, 2006; Mimeault, Pommery, Wattez, Bailly, & Henichart, 2003). Further work in MCL showed that cannabinoids induced CerS3 and CerS6 expression.…”

Antitumor Cannabinoid Chemotypes: Structural Insights

“…WIN55,212-2, a CB1R/CB2R dual agonist, has been one of the most widely used pharmacological tools to get insights into the endocannabinoid system. WIN55,212-2 ( Table 1 ) inhibits cell proliferation and migration in triple-negative breast cancer (Qamri et al, 2009); in prostate cancer (Morell et al, 2016); in gastric cancer (Xian et al, 2016); in hepatocellular carcinoma (Xu et al, 2015); in lung cancer, testicular cancer, and neuroblastoma (Müller et al, 2017); in myeloma (Barbado et al, 2017); and in renal carcinoma (Khan et al, 2018). Most of these results were confirmed in vivo in various mouse model systems.…”