Cannabinoid Receptors Are Overexpressed in CLL but of Limited Potential for Therapeutic Exploitation

Abstract

The cannabinoid receptors 1 and 2 (CNR1&2) are overexpressed in a variety of malignant diseases and cannabinoids can have noteworthy impact on tumor cell viability and tumor growth. Patients diagnosed with chronic lymphocytic leukemia (CLL) present with very heterogeneous disease characteristics translating into highly differential risk properties. To meet the urgent need for refinement in risk stratification at diagnosis and the search for novel therapies we studied CNR expression and response to cannabinoid treatment in CLL. Expression levels of CNR1&2 were determined in 107 CLL patients by real-time PCR and analyzed with regard to prognostic markers and survival. Cell viability of primary CLL cells was determined in suspension and co-culture after incubation in increasing cannabinoid concentrations under normal and reduced serum conditions and in combination with fludarabine. Impact of cannabinoids on migration of CLL cells towards CXCL12 was determined in transwell plates. We found CNR1&2 to be overexpressed in CLL compared to healthy B-cells. Discriminating between high and low expressing subgroups, only high CNR1 expression was associated with two established high risk markers and conferred significantly shorter overall and treatment free survival. Viability of CLL primary cells was reduced in a dose dependent fashion upon incubation with cannabinoids, however, healthy cells were similarly affected. Under serum reduced conditions, no significant differences were observed within suspension and co-culture, respectively, however, the feeder layer contributed significantly to the survival of CLL cells compared to suspension culture conditions. No significant differences were observed when treating CLL cells with cannabinoids in combination with fludarabine. Interestingly, biologic activity of cannabinoids was independent of both CNR1&2 expression. Finally, we did not observe an inhibition of CXCL12-induced migration by cannabinoids. In contrast to other tumor entities, our data suggest a limited usability of cannabinoids for CLL therapy. Nonetheless, we could define CNR1 mRNA expression as novel prognostic marker.

Medical Cannabis in Pediatric Oncology: Friend or Foe?

“…Another investigation into the expression and potential clinical utility of CB1 and CB2 in chronic lymphocytic leukemia (CLL) patients found that high CB1 expression (as measured via mRNA levels) was correlated with poor outcomes, and cultures of patient cells and normal cell controls from healthy patients showed decreased viability in response to cannabinoid treatment (primarily synthetic). This effect was not correlated with expression levels of CB1 or CB2, suggesting the involvement of other receptors despite the use of synthetic cannabinoids designed to target CB1 or CB2 specifically [ 55 ].…”

“…Treatment of cancer cells with a variety of synthetic and plant-derived cannabinoids was found to increase cell proliferation by upregulating the ERK1/2 and Akt survival pathways via EGFR activation [ 54 ]. High CB1 and CB2 levels have also been found in cases of chronic lymphocytic leukemia (CLL) [ 55 ]. Many TRP channels are upregulated in different cancers, and the potential to exploit them in cancer treatment, though not with cannabinoids, has been explored [ 56 ].…”

Anti-cancer activities of Schedule E1 drugs used in ayurvedic formulations

“…Chemically induced Hepatocellular carcinoma using Diethyl nitrosamine expressed upregulation of CB1 receptors [ 52 ] whereas in normal hepatocellular carcinoma overexpression of both CB1 and CB2 receptors were reported [ 58 ]. The non-small cell lung carcinoma showed the activation of Akt signaling pathway and Matrix metallo peptidase-9 (MMP-9) expression whereas the chronic lymphocytic leukemia was found to act by CB1 receptor expression along with the expression of high risk markers [ 59 , 60 ]. In Pancreatic cells the cannabinoids were found to induce apoptosis through CB2 receptors via ceramide dependent pathway [ [61] , [62] , [63] ].…”

The Interplay between the Immune and the Endocannabinoid Systems in Cancer

“…Activation of both CB1 and CB2 receptors of MCL cells induces the accumulation of ceramide and apoptosis [ 269 ]. In chronic lymphocytic leukemia (CLL), CB receptors are overexpressed compared to healthy B-cells and CB1 could be a novel prognostic marker [ 270 ].…”