The antitumor potential of the endocannabinoid-reuptake inhibitor OMDM-2 alone and in combination with cytostatic drugs

Cannabis sativa has been used as medicinal plant since ancient times. Its major psychotropic ingredient ?9-tetrahydrocannabinol (THC) was characterized about 50 years ago, but only in the 90s endogenous counterparts of THC were discovered. These endogenous counterparts are collectively termed endocannabinoids (eCBs). They are increasingly emerging as widespread, complex and highly versatile signaling molecules controlling basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation (1). This makes them interesting in the treatment of cancer. Indeed, THC potential antitumor activity has been demonstrated. Targeting the eCBs as new strategy should avoid clinical and ethical considerations which limit the use of the direct agonists. We investigated the cytotoxity of the designated endocannabinoid reuptake inhibitor OMDM-2 alone and in combination with cytotoxic drugs and with the natural anticancer agent curcumin.In-vivo experiments in the Ehrlich-Ascites mouse model provided evidence for an antitumor potential of OMDM-2. In-vitro MCF-7 (breast cancer cells) and U-87 (glioma cells) were used to test the antiproliferative activity of OMDM-2 alone and in combination with standard chemotherapeutic drugs paclitaxel and temozolomide, respectively. Our combinations were evaluated by using different methods; isobole, combination index, dose reduction index. The results indicated that the addition of OMDM-2 to the chemoresistant breast and glioma cancer cells not only increased their sensitivity but also decreased the required dose of benchmark chemotherapeutics.Increasing evidence substantiate the notion that combination therapies utilizing both-molecules targeting the endocannabinoid system in addition to natural anticancer agents or benchmark chemotherapeutics are a worthwhile option to be systematically explored in the treatment of cancer