Targeting the endocannabinoid system in colorectal cancer

The endogenous cannabinoid system, comprising the cannabinoid receptors, their endogenous ligands (e.g. anandamide) and the enzymes regulating endocannabinoid biosynthesis and degradation, is an almost ubiquitous signaling system involved in the control of several physio-pathological conditions. Modulation of endocannabinoid tone has proven to hold several therapeutic promise in the treatment of a wide range of pathological processes. In this framework, given the ubiquity of the endocannabinoids and their receptors and their regulating action on proteins involved in cell fate control, there has been increasing evidence for a role of the endocannabinoid system also into neoplastic transformation and an interest to exploit it for a potential therapeutic application. However, despite several reports on endocannabinoids' properties, little is known concerning the endogenous function of the endocannabinoid system and in particular of CB1 signaling in the regulation of tumor growth. A deregulation of the endocannabinoid system occurs in colorectal cancer (CRC). Loss of cannabinoid receptor 1 expression has been associated with colon tumor progression through a mechanism of epigenetic silencing, suggesting a role for CB1 as a tumor suppressor. A stable analogue of the endocannabinoid anandamide was utilized as a critical tool to characterize the basal functions of endocannabinoid system and CB1 signaling in CRC. Anandamide emerged as suppressor of colon tumor growth, since up regulation of CB1 receptor expression based on transcriptional regulation acting on its gene promoter affected CRC proliferation. However, a rapid anandamide metabolism has been identified in CRC, thus limiting this protective mechanism. As a consequence, an indirect targeting of anandamide degradative enzyme fatty acid amide hydrolase to maintain a local endocannabinoid tone has been proved. FAAH inhibition has been demonstrated to affect CRC proliferation through cell cycle machinery deregulation, DNA damage signaling pathway activation and late programmed cell death induction. Oxaliplatin in combination with 5-Fluorouracil and leucovorin (FOLFOX) has been approved for metastatic CRC therapy. Despite clinical success, patients who initially respond to chemotherapeutics may subsequently become refractory, directing the attention towards alternative strategies, including the use of combined therapies. A combinatorial approach has proven effective since FAAH inhibition sensitizes CRC cells to targeted therapies, thus representing a valid strategy to overcome drug resistance and side effects.