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The expression level of CB1 and CB2 receptors determines their efficacy at inducing apoptosis in astrocytomas

Eiron Cudaback1, William Marrs, Thomas Moeller

  • 1Department of Pharmacology, University of Washington, Seattle, Washington, United States of America.

Plos One
|January 22, 2010
PubMed
Abstract

Insights

Cannabinoids show potential for treating astrocytomas, but receptor levels matter. High CB(1) and CB(2) receptor expression can block cannabinoid-induced apoptosis unless AKT is inhibited or high concentrations are used.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cannabinoids are investigated for their potential in treating tumors, including astrocytomas.
  • The precise role of cannabinoid receptors (CB1 and CB2) in mediating these therapeutic effects remains unclear.

Purpose of the Study:

  • To investigate the role of CB1 and CB2 receptor expression levels in cannabinoid-induced apoptosis in astrocytoma cells.
  • To elucidate the signaling pathways involved in cannabinoid response in astrocytoma.

Main Methods:

  • Generation of astrocytoma subclones with varying expression levels of CB1 and CB2 receptors.
  • Analysis of apoptosis induction by cannabinoids in relation to receptor expression and downstream signaling pathways (ERK1/2 and AKT).

Main Results:

  • Cannabinoids induced apoptosis in astrocytoma cells with low CB1/CB2 receptor levels coupled to ERK1/2.
  • Cells with high CB1/CB2 receptor levels, coupled to the prosurvival AKT pathway, did not undergo apoptosis.
  • High concentrations of cannabinoids induced apoptosis in all cell lines, independent of CB1/CB2 and AKT, but still involving ERK1/2.

Conclusions:

  • High expression of CB1 and CB2 receptors in malignant astrocytomas may limit cannabinoid efficacy.
  • Therapeutic use of cannabinoids could be feasible if AKT is inhibited or if high concentrations are used to bypass receptor-dependent pathways.
  • The ERK1/2 pathway remains a critical mediator of cannabinoid-induced apoptosis, even at high concentrations.

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