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First published on June 5, 2006; DOI: 10.1124/mol.106.023937

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Received for publication February 28, 2006.
Revised June 5, 2006.
Accepted for publication June 5, 2006.

Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression

Robert J McKallip 1*, Wentao Jia 2, Jerome Schlomer 2, James W. Warren 3, Prakash S Nagarkatti 3, Mitzi Nagarkatti 3

1 USC school of medicine 2 VCU 3 USC School of Medicine

* Address correspondence to: E-mail: rmckallip{at}gw.med.sc.edu

Abstract

In the current study, we examined the effects of the non-psychoactive cannabinoid, cannabidiol, on the induction of apoptosis in leukemia cells. Exposure of leukemia cells to cannabidiol led to CB2-mediated reduction in cell viability and induction in apoptosis. Furthermore, cannabidiol treatment led to a significant decrease in tumor burden and an increase in apoptotic tumors in vivo. Mechanistically, cannabidiol exposure resulted in activation of caspase-8, caspase-9, and caspase-3, cleavage of PARP and a decrease in full-length Bid, suggesting possible cross-talk between the intrinsic and extrinsic apoptotic pathways. The role of the mitochondria was further suggested as exposure to cannabidiol led to loss of mitochondrial membrane potential and release of cytochrome C. Interestingly, cannabidiol exposure led to an increase in reactive oxygen species (ROS) production as well as an increase in the expression of the NAD(P)H oxidases, NOX4 and p22phox. Furthermore, cannabidiol-induced apoptosis and ROS levels could be blocked by treatment with the ROS scavengers, or the NAD(P)H oxidase inhibitors. Finally, cannabidiol exposure led to a decrease in the levels of p-p38 MAPK, which could be blocked by treatment with a CB2-selective antagonist or ROS scavenger. Together, the results from this study reveal that cannabidiol, acting through CB2 and regulation of NOX4 and p22phox expression, may be a novel and highly selective treatment for leukemia.


Key words: Cannabinoid, Apoptosis, Oxidative stress/antioxidants, Mechanisms of cell killing/apoptosis


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S. D. McAllister, R. T. Christian, M. P. Horowitz, A. Garcia, and P.-Y. Desprez
Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells
Mol. Cancer Ther., November 1, 2007; 6(11): 2921 - 2927.
[Abstract] [Full Text] [PDF]


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