Molecular Mechanisms of Cannabinoids as Anti-cancer Agents



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Cancer is a growing health concern world-wide and is the second most common cause of death after heart diseases. Current treatment strategies such as surgery, chemotherapy and radiation provide some relief to cancer patients but the toxic side effects associated with chemotherapy and radiation often lead to further adverse health effects. Hence there is a need for drugs with better safety profile and improved efficacy.

Cannabinoids are a group of compounds with several therapeutic properties and besides their appetite stimulant, anti-emetic and analgesic effects, cannabinoids can inhibit tumor growth, survival and metastasis. The mechanisms of action of cannabinoids as anticancer agents are highly complex and not completely understood. Studies from our laboratory indicate that the specificity protein (Sp) transcription factors, Sp1, Sp3 and Sp4 that belong to the Sp/KLF family of transcription factors are overexpressed in many tumors and regulate critical factors responsible for cancer cell proliferation, growth, angiogenesis and survival. Hence, we hypothesized that cannabinoids elicit their responses on cancer cells by downregulating the expression of Sp proteins and Sp-regulated gene products. Treatment of colon and prostate cancer cells with the cannabinoids WIN and cannabidiol (CBD) inhibited cancer cell proliferation, induced apoptosis and downregulated Sp proteins and Sp-dependent genes. Furthermore, we demonstrated that WIN and CBD-mediated induction of apoptosis and repression of Sp proteins were mediated by phosphatases and that the phosphatase involved in WIN- dependent downregulation of Sp proteins was protein phosphatase 2A (PP2a). In addition WIN induced expression of ZBTB-10, an Sp repressor and downregulated microRNA-27a (miR27a) and these effects were PP2a-dependent indicating that WIN transcriptionally represses Sp protein expression by activating the phosphatase, PP2a.

We also investigated the effects of 1,1-bis(3'-indolyl)-1-(p-bromophenyl)methane (DIM-C-pPhBr) and the 2,2'-dimethyl analog (2,2'-diMeDIM-C-pPhBr), on survivin expression in colon and pancreatic cancer cells. Survivin is an anti-apoptotic protein associated with cancer cell survival and confers radiation-resistance in patients receiving radiotherapy. In addition radiation induces survivin, leading to radioresistance in tumors. In this study we demonstrated that DIM-C-pPhBr and 2,2'-diMeDIM-C-pPhBr inhibit cell proliferation and induce apoptosis in colon and pancreatic cancer cells and in combination with radiotherapy, these drugs suppress radioresistance by inhibiting radiation induced survivin.