Targeting astrocytomas with cannabinoids

The last quarter century has bore witness to great advances in both the detection and treatment of numerous cancers. Even so, malignancies of the central nervous system, especially high grade astrocytomas, continue to thwart our best efforts toward effective chemotherapeutic strategies. With prognosis remaining bleak, the time for serious consideration of alternative therapies has arrived. Various preparations of the marijuana plant, Cannabis sativa, and related synthetic and endogenous compounds, may constitute just such an alternative. Cannabinoids, although much maligned historically for their psychotropic effects and clear abuse potential, have long been used medicinally and are now staging an impressive comeback as recent studies have begun to explore their powerful anti-tumoral properties. Specifically, cannabinoids represent unique compounds for treating high-grade, astrocytic tumors. Whether cannabinoid receptors, CB1 and/or CB2, mediate this therapeutic effect is unclear. My research focused on the role that CB1 and CB2 receptors play in cannabinoid-induced astrocytoma cell death, as well as the nature of the cytotoxicity induced. To address these questions I generated astrocytoma subclones that express set levels of CB1 and CB2, and found that cannabinoids induce apoptosis only in cells expressing low levels of receptors that couple to ERK1/2. In contrast, cannabinoids do not induce apoptosis in cells expressing high levels of receptors because these now also couple to the prosurvival signal AKT. Remarkably, cannabinoids applied at high concentration induce apoptosis in all subclones independently of CB1, CB2 and AKT, but still through a mechanism involving ERK1/2. Thus the high expression level of CB1 and CB2 receptors commonly found in malignant astrocytomas precludes the use of cannabinoids as therapeutics, unless AKT is concomitantly inhibited, or cannabinoids are applied at concentrations that bypass CB1 and CB2 receptors yet still activate ERK1/2. Based on my findings, I propose the continued, intense investigation of cannabinoid efficacies as novel anti-cancer agents, especially in models recapitulating such properties within the unique environment of the brain.