Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis

Abstract

Among a variety of phytocannabinoids, Δ-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most promising therapeutic compounds. Besides the well-known palliative effects in cancer patients, cannabinoids have been shown to inhibit in vitro growth of tumor cells. Likewise, the major endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), induce tumor cell death. The purpose of the present study was to characterize cannabinoid elements and evaluate the effect of cannabinoids in endometrial cancer cell viability. The presence of cannabinoid receptors, transient receptor potential vanilloid 1 (TRPV1), and endocannabinoid-metabolizing enzymes were determined by qRT-PCR and Western blot. We also examined the effects and the underlying mechanisms induced by eCBs and phytocannabinoids in endometrial cancer cell viability. Besides TRPV1, both EC cell lines express all the constituents of the endocannabinoid system. We observed that at concentrations higher than 5 μM, eCBs and CBD induced a significant reduction in cell viability in both Ishikawa and Hec50co cells, whereas THC did not cause any effect. In Ishikawa cells, contrary to Hec50co, treatment with AEA and CBD resulted in an increase in the levels of activated caspase -3/-7, in cleaved PARP, and in reactive oxygen species generation, confirming that the reduction in cell viability observed in the MTT assay was caused by the activation of the apoptotic pathway. Finally, these effects were dependent on TRPV1 activation and intracellular calcium levels. These data indicate that cannabinoids modulate endometrial cancer cell death. Selective targeting of TPRV1 by AEA, CBD, or other stable analogues may be an attractive research area for the treatment of estrogen-dependent endometrial carcinoma. Our data further support the evaluation of CBD and CBD-rich extracts for the potential treatment of endometrial cancer, particularly, that has become non-responsive to common therapies.

Cannabinoids in Gynecological Diseases

“…Expression of all components of the ECS, including TRPV1, was detected in the cells. Additionally, treatment of the cells with AEA or CBD (>5 µM) resulted in a reduced cell viability that was linked to an increase in ROS production and caspase-3/-7 activity [117]. The findings regarding the proapoptotic action of AEA are well in accordance with the observations by Contassot et al [89], who described AEA-driven cancer cell apoptosis via TRPV1 activation.…”

“…The same effects could be detected after matrix metalloproteinase-9 silencing [116]. More recently, the involvement of THC and CBD in endometrial cancer was investigated in 2 model cell lines, i.e., Ishikawa and Hec50co cells [117]. Expression of all components of the ECS, including TRPV1, was detected in the cells.…”

A Guide to Targeting the Endocannabinoid System in Drug Design

“…Concerning eCBs, they generally exert tumor-suppressive effect, based on clinical observations [272]. In vitro, AEA was demonstrated to decrease invasion and metastasis by upregulating a tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) [273] and to induce apoptosis via oxidative stress in COX-2- [274] and TRPV1-dependent manner [275]. 2-AG (20 mg/kg/day) showed similar properties in the rodent model, at the same time suppressing tumor immune-mediated surveillance [276].…”

Ion channels as therapeutic antibody targets

“…TRPV1 is overexpressed in many tumor types, including endometrial, 260 thyroid, 261 breast, 262 astrocytoma, 263 prostate, 264 pancreas, 265 colon, 266 melanoma 267 and bladder. 267 TRPV1 is activated by capsaicin and is probably the most well-known TRP channel targeted for pain with marketed products, such as Qutenza® (Acorda Therapeutics) and Zuacta TM (Sanofi), both of which are capsaicin-based.…”