Involvement of the Endocannabinoid System in the Development and Treatment of Breast Cancer

Studies to evaluate the interaction of the synthetic cannabinoid WIN55,212-2 (WIN2) and ionizing radiation have led to preliminary results implicating a novel site of action of WIN2 in the MCF-7 breast cancer model. In previous reports, WIN2 was found to stereoselectively inhibit the growth of breast cancer cells in a dose-dependent but cannabinoid receptor-independent mechanism. Experiments described in this report evaluated antiproliferative mechanisms of WIN2 treatment both alone and in combination with ionizing radiation (IR). Evaluation of autophagy, apoptosis and necrotic mechanism failed to indicate that WIN2 promoted death of the tumor cells. Autophagy was induced both for radiation alone, WIN2 alone and WIN2 + radiation, but did not appear to be involved in the antiproliferative mechanisms of either treatment. Senescence, quantified by β-galactosidase staining, and DNA damage, quantified by γH2AX formation, confirmed that radiation treatment induced senescent growth arrest both alone and in combination with WIN2; however, WIN2 was unable to alter the magnitude of senescent growth arrest induced by IR. Comparison of γH2AX levels at 1 and 24 h also showed that WIN2 did not alter the rate of DNA repair after radiation treatment. These data assessing cell death and senescence combined with additional temporal cell count studies indicated that WIN2 induces growth arrest but not cell death. It was further concluded that augmentation of IR induced antiproliferative effects by WIN2 occur from the parallel induction of both senescent and classical growth arrest responses in the breast tumor cells.