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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1214-1221.
Prepublished online as a Blood First Edition Paper on September 28, 2004; DOI 10.1182/blood-2004-03-1182.
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Submitted March 29, 2004
Accepted September 10, 2004
Cannabis induced cytotoxicity in leukaemic 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 M Liu*
New Drug Study Group, St Bartholomew's Hospital (SBH), London, United Kingdom; Dept Medical Oncology, St Bartholomew's Hospital (SBH), London, United Kingdom
Centre for Cancer Therapeutics, Institute of Cancer Research, Surrey, United Kingdom
Dept Medical Oncology, St Bartholomew's Hospital (SBH), London, United Kingdom
Dept Medical Oncology, Charterhouse Square, London, United Kingdom
New Drug Study Group, St Bartholomew's Hospital (SBH), London, United Kingdom
Barry Reed Oncology Laboratory, London, United Kingdom
* Corresponding author; email: wai.liu{at}icr.ac.uk.
 9-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 leukaemic 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 utilised 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 1X IC50 concentrations, and as early as six hours after exposure to the drug. These effects were seen in leukaemic 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 MAPK signal transduction pathways. Both apoptosis and gene expression changes were altered independent of p53 and the CB-Rs.
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