Research Article: The Expression Level of CB1 and CB2 Receptors Determines Their Efficacy at Inducing Apoptosis in Astrocytomas

Date Published: January 14, 2010

Publisher: Public Library of Science

Author(s): Eiron Cudaback, William Marrs, Thomas Moeller, Nephi Stella, Joseph Najbauer.

Abstract: Cannabinoids represent unique compounds for treating tumors, including astrocytomas. Whether CB1 and CB2 receptors mediate this therapeutic effect is unclear.

Partial Text: Cannabinoids produce the majority of their biological effects by activating two receptors: CB1 and CB2. In healthy brain, CB1 is expressed by neurons, astrocytes and neural progenitor cells, whereas CB2 is only expressed by a small population of neurons located in the brain stem [1], [2]. Activation of CB1 and CB2 receptors regulates fundamental physiological processes, including neurotransmission efficacy, astrocytic function, and the fate and proliferation rate of neural progenitor cells [3], [4]. Thus, because these receptors regulate such fundamental physiological processes, extensive effort has been invested toward understanding how cannabinoid compounds activate CB1 and CB2 receptors, as well as regulate the signal transduction mechanisms they couple to, with the goal of developing novel therapeutics to treat various neuropathologies [5], [6].

While many laboratories have reported that cannabinoids induce apoptosis in various tumor subtypes, including astrocytomas, the requirement for CB1 and CB2 in mediating this therapeutic effect has not yet been demonstrated. This point is especially relevant when considering that many of these studies used high concentrations of cannabinoids known to bypass CB1 and CB2 receptor activation. Here we demonstrate that cannabinoid receptors and ERK1/2 indeed mediate this therapeutic effect, but only when these compounds are applied at submicromolar concentrations and the expression level of these receptors remains low. Conversely, high concentrations of cannabinoids kill all astrocytoma subclones independently of CB1, CB2 and AKT, yet still through a mechanisms involving ERK1/2. We also show that increased expression of CB1 and CB2 receptor allows for their coupling to additional kinases, especially AKT, the result of which eliminates the ability of cannabinoids to induce apoptosis even though these receptors still couple to ERK1/2.



0 0 vote
Article Rating
Notify of
Inline Feedbacks
View all comments