Effect of phytocannabinoids on androgen deprivation therapy in a high-fat diet-exacerbated prostate cancer

Prostate cancer (PCa) is the second most frequent cause of tumour-associated mortality worldwide. Tumour growth depends on androgens, therefore, the mainstay treatment, especially for advanced tumour, is based on androgen deprivation therapy (ADT). Despite accumulation of abdominal fat and metabolic syndrome development as reported side effects in patients receiving ADT, androgen blockade is a backbone therapy also in obese PCa patients. Increasingly, studies have pointed out that obesity is closely linked to the occurrence, development and aggressiveness of PCa. Western diets (diet with high fat and sugar) has been suggested to promote prostate tumour carcinogenesis and contributing to negative prognosis. However, the underlying mechanisms are still poorly understood. Gastrointestinal microbiome has been shown to play a major role in the pathogenesis of several diseases and to play a role as regulator of androgen metabolism potentially contributing to PCa development and/or pharmacological outcome of ADT. Several studies consider certain phytocannabinoids promising anti-cancer agents and controllers of food intake and lipid metabolism. Herein, we investigated the effect of phytocannabinoids (CBD+CBG), alone and combined with the anti-androgen enzalutamide, on the tumour the progression in transgenic adenocarcinoma mouse prostate model (TRAMP) under high fat diet (HFD) and regular diet (RD). Histopathological analysis and gut microbiota profiling showed that HFD exacerbated PCa development and induced gut microbiota dysbiosis increasing the Firmicutes to Bacteroidetes ratio. Single treatments with anti-androgen or phytocannabinoids significantly inhibited tumour development only in RD-fed mice. Combined treatments were effective in mice under both diet regimens. As for the associated gut microbiota in HFD-fed mice, enzalutamide, both alone and in combination with phytocannabinoids, reverted the lowered levels of phylum Bacteroidetes. With respect to enzalutamide treatment alone its combined treatment with CBD:CBG was associated with increased abundance of bacterial families such as Anaerosporobacter, Roseburia, Lactobacillus and reduced of Turicibacter Clostridium sensu stricto 1, Phocea, Bilophila and Acetanaerobacterium. The study reveals that phytocannabinoids combined with enzalutamide improves inhibition of tumour growth in HFD-exacerbated prostate cancer and modifies gut microbiota composition. These findings indicate a novel, more beneficial with respect to monotherapy, therapeutic approach for PCa progression worsened by obesity.