Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway
- Thomas Powles,
- Robert te Poele,
- Jonathan Shamash,
- Tracy Chaplin,
- David Propper,
- Simon Joel,
- Tim Oliver, and
- Wai Man Liu
+ Author Affiliations
Abstract
Δ9-Tetrahydrocannabinol (THC) is the
active metabolite of cannabis. THC causes cell death in vitro through
the activation
of complex signal transduction pathways. However,
the role that the cannabinoid 1 and 2 receptors (CB1-R and CB2-R) play
in
this process is less clear. We therefore
investigated the role of the CB-Rs in mediating apoptosis in 3 leukemic
cell lines
and performed microarray and immunoblot analyses to
establish further the mechanism of cell death. We developed a novel
flow
cytometric technique of measuring the expression of
functional receptors and used combinations of selective CB1-R and CB2-R
antagonists and agonists to determine their
individual roles in this process. We have shown that THC is a potent
inducer of
apoptosis, even at 1 × IC50 (inhibitory
concentration 50%) concentrations and as early as 6 hours after exposure
to the drug. These effects were seen
in leukemic cell lines (CEM, HEL-92, and HL60) as
well as in peripheral blood mononuclear cells. Additionally, THC did not
appear to act synergistically with cytotoxic agents
such as cisplatin. One of the most intriguing findings was that
THC-induced
cell death was preceded by significant changes in
the expression of genes involved in the mitogen-activated protein kinase
(MAPK) signal transduction pathways. Both apoptosis
and gene expression changes were altered independent of p53 and the
CB-Rs.
- Submitted March 29, 2004.
- Accepted September 10, 2004.
- Copyright © 2005 by The American Society of Hematology
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