EFFECT OF NON-PSYCHOTROPIC CANNABINOIDS ON TUMOUR GROWTH IN HORMONE REFRACTORY PROSTATE CANCER

Prostate cancer (PCa) represents a huge worldwide health burden, according to 2019 statistics of the American cancer society1. As PCa is hormone dependent, the first line treatment for the advanced and metastatic tumour is androgen deprivation therapy (ADT). However, the majority of tumours develop a hormone refractory PCa phenotype (HRPC), and become resistant to hormone therapy. Herein, we investigated the development of the hormone refractory (AR-independent) phase of PCa with respect to metabolic and oncogenic modulations, and study the therapeutic effect of non-psychotropic phytocannabinoids, such as CBD and CBG (alone or in combination), by using a prostate cancer model (TRAMP) that resembles the human disease. First, we demonstrated that phytocannabinoids inhibit both primary and advanced PCa in TRAMP model. Remarkably, we developed in vivo and in vitro models of HRPC that showed unique metabolic features, and that were established from TRAMP mice and TRAMP-C2 cell line using the second-generation AR inhibitor, enzalutamide (MDV3100). Significantly, we found that CBD was particularly metabolically active in arresting the HRPC phase. In this context, CBD perturbed the metabolic programming of PCa cells especially by increasing glycolysis and by inhibiting mitochondria oxidative phosphorylation in HRPC cells. Here we showed how CBD acted on mitochondria by elevating level of mtROS and by decreasing ATP production. CBD-mediated release of mtROS is responsible for the consequent up regulation of the transcription factor HIF-1?, which contributes to sustain a hyper-glycolytic phenotype in HRPC cells, and it promotes acidosis-induced apoptosis via BNIP3 up regulation. Moreover, the low ATP production induced by CBD in HRPC cells was accompanied by up regulation of AMPK, which activates the autophagic activated protein ULK. As a consequence, the overall effect of CBD on metabolic reprogramming may disrupt the oncogenic signalling in HRPC tumour cells by activating PTEN and inhibiting pAkt. Our study establishes new in vivo and in vitro models of HRPC, which were achieved by using TRAMP mice and TRAMP cells, and sheds the light on novel metabolic targets and therapeutic interventions in HRPC. The study provides the basis for further investigations supporting the hypothesis that phytocannabinoids can be used for metabolic interventions and adjuvant therapy for HRPC.