Abstract 4658: Delta9-Tetrahydrocannabinol induces apoptosis via Cannabinol Receptor 1 and modulates methylation of oncogenes and tumorsuppressors in blasts derived from patients with acute lympoblastic or myeloid leukemia
Authors: Kampa Kerstin M. , salitzky olaf , walter michael , salih helmut , Mueller-Huebenthal Boris , Schittenhelm Marcus 
Published: August 2012

Abstract
Some cannabinol derivatives are said to possess antitumor efficacy. We have evidence that the CB1/2 cannabinoid receptor agonist Delta9-Tetrahydrocannabinol (THC), the major psychoactive component of marijuana, may have contributed to disease control in a patient with acute myeloid leukemia. We speculated that THC may induce apoptosis in native leukemic blasts and thus treated various leukemia cell lines and ex vivo blasts derived from patients with either acute lymphoblastic or myeloid leukemia in dilution series with THC. The antiproliferative effect was measured using an XTT-based assay. Induction of apoptosis was assessed by annexinV-based immunofluorescence analysis. The CB1 antagonist LY320135 or JTE-907, a selective CB2 inverse ligand agonist, were used to confirm involvement of CB1 (mainly expressed in brain tissue) or CB2 (expression in hematologic/lymphoid cells). THC was obtained with permission of the Bundesopiumstelle, Germany. Indeed, we demonstrate potent antiproliferative and proapoptotic efficacy of Delta9-THC in a dose dependent manner in leukemia cell lines of lymphoid and myeloid origin. Pretreatment with LY320135, but not with JTE-907, resulted in a dramatic abrogation of the antileukemic effect seen with THC monotherapy, arguing that THC-induced apoptosis is mediated via the cannabinoid receptor CB1. Besides a proapoptotic effect, THC was able to abrogate cellular differentiation blockage as observed in a change of morphology. Of note, THC was able to induce apoptosis in a subset of leukemia samples derived from patients with acute myeloid (mainly undifferentited AML) or lymphoblastic leukemia. Due to the patient cohort responsive to THC therapy, we speculated that epigenetic modifications might be associated with MLL (mixed lineage leukemia) methyltransferase function. In a global DNA methylation gene array, we could demonstrate that THC leads to modulation of methylation status of histone deacetylases, oncogenes and tumorsuppressors, some reported to be regulated by MLL. Ongoing work is focussing on validation whether THC treatment can be linked to MLL activity using an siRNA approach. In conclusion, while not being able to directly correlate the disease course of the above described patient to marijuana abuse, our in vitro results nevertheless demonstrate that THC mediates antileukemic activity in blasts of some patients ex vivo including that of our patient. Clinical evaluation of cannabinol receptor agonists as low-toxic agents could thus be considered in selected cases of patients with acute leukemia and this approach should further be followed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4658. doi:1538-7445.AM2012-4658