Cannabinoids May Inhibit Cancer Cell Invasion
Cannabinoids may suppress tumor invasion in highly invasive cancers, according to a study published online December 25 in the Journal of the National Cancer Institute.
Schematic representation of TIMP-1 structure. TIMP1 contains 12 cysteine residues which form six loop structures through disulfide bonds. The N-terminus of TIMPs 1-4 binds to the catalytic domain of most activated MMPs and inhibits function. The C-terminus of TIMP1 and TIMP2 binds to the hemopexin domain of proMMP2 and proMMP9, respectively; this binding regulates MMP function.
Cannabinoids, the active components in marijuana, are used to reduce the side effects of cancer treatment, such as pain, weight loss, and vomiting, but there is increasing evidence that they may also inhibit tumor cell growth. However, the cellular mechanisms behind this are unknown.
Robert Ramer, Ph.D., and Burkhard Hinz, Ph.D., of the University of Rostock in Germany investigated whether and by what mechanism cannabinoids inhibit tumor cell invasion.
Cannabinoids did suppress tumor cell invasion and stimulated the expression of TIMP-1, an inhibitor of a group of enzymes that are involved in tumor cell invasion.
“To our knowledge, this is the first report of TIMP-1-dependent anti-invasive effects of cannabinoids. This signaling pathway may play an important role in the antimetastatic action of cannabinoids, whose potential therapeutic benefit in the treatment of highly invasive cancers should be addressed in clinical trials,” the authors write.
J Natl Cancer Inst. 2007 Dec 25
Inhibition of Cancer Cell Invasion by Cannabinoids via Increased Expression of Tissue Inhibitor of Matrix Metalloproteinases-1.
Ramer R, Hinz B.
Affiliation of authors: Institute of Toxicology and Pharmacology, University of Rostock, Rostock, Germany.
Background Cannabinoids, in addition to having palliative benefits in cancer therapy, have been associated with anticarcinogenic effects. Although the antiproliferative activities of cannabinoids have been intensively investigated, little is known about their effects on tumor invasion. Methods Matrigel-coated and uncoated Boyden chambers were used to quantify invasiveness and migration, respectively, of human cervical cancer (HeLa) cells that had been treated with cannabinoids (the stable anandamide analog R(+)-methanandamide [MA] and the phytocannabinoid Delta(9)-tetrahydrocannabinol [THC]) in the presence or absence of antagonists of the CB(1) or CB(2) cannabinoid receptors or of transient receptor potential vanilloid 1 (TRPV1) or inhibitors of p38 or p42/44 mitogen-activated protein kinase (MAPK) pathways. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting were used to assess the influence of cannabinoids on the expression of matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs). The role of TIMP-1 in the anti-invasive action of cannabinoids was analyzed by transfecting HeLa, human cervical carcinoma (C33A), or human lung carcinoma cells (A549) cells with siRNA targeting TIMP-1. All statistical tests were two-sided. Results Without modifying migration, MA and THC caused a time- and concentration-dependent suppression of HeLa cell invasion through Matrigel that was accompanied by increased expression of TIMP-1. At the lowest concentrations tested, MA (0.1 muM) and THC (0.01 muM) led to a decrease in invasion (normalized to that observed with vehicle-treated cells) of 61.5% (95% CI = 38.7% to 84.3%, P < .001) and 68.1% (95% CI = 31.5% to 104.8%, P = .0039), respectively. The stimulation of TIMP-1 expression and suppression of cell invasion were reversed by pretreatment of cells with antagonists to CB(1) or CB(2) receptors, with inhibitors of MAPKs, or, in the case of MA, with an antagonist to TRPV1. Knockdown of cannabinoid-induced TIMP-1 expression by siRNA led to a reversal of the cannabinoid-elicited decrease in tumor cell invasiveness in HeLa, A549, and C33A cells. Conclusion Increased expression of TIMP-1 mediates an anti-invasive effect of cannabinoids. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.