Mahmoud Ali Mokhtar, Kostrzewa Magdalena, Marolda Viviana, Cerasuolo Marianna, Maccarinelli Federica, Coltrini Daniela, Rezzola Sara, Giacomini Arianna, Mollica Maria Pina, Motta Andrea, Paris Debora, Zorzano Antonio, Di Marzo Vincenzo, Ronca Roberto, Ligresti Alessia
National Research Council of Italy, Institute of Biomolecular Chemistry, Pozzuoli, Italy.
University of Portsmouth, School of Mathematics and Physics, Hampshire PO1 3HF, UK.
Pharmacol Res. 2023 Mar;189:106683. doi: 10.1016/j.phrs.2023.106683. Epub 2023 Feb 1.
In spite of the huge advancements in both diagnosis and interventions, hormone refractory prostate cancer (HRPC) remains a major hurdle in prostate cancer (PCa). Metabolic reprogramming plays a key role in PCa oncogenesis and resistance. However, the dynamics between metabolism and oncogenesis are not fully understood. Here, we demonstrate that two multi-target natural products, cannabidiol (CBD) and cannabigerol (CBG), suppress HRPC development in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model by reprogramming metabolic and oncogenic signaling. Mechanistically, CBD increases glycolytic capacity and inhibits oxidative phosphorylation in enzalutamide-resistant HRPC cells. This action of CBD originates from its effect on metabolic plasticity via modulation of VDAC1 and hexokinase II (HKII) coupling on the outer mitochondrial membrane, which leads to strong shifts of mitochondrial functions and oncogenic signaling pathways. The effect of CBG on enzalutamide-resistant HRPC cells was less pronounced than CBD and only partially attributable to its action on mitochondria. However, when optimally combined, these two cannabinoids exhibited strong anti-tumor effects in TRAMP mice, even when these had become refractory to enzalutamide, thus pointing to their therapeutical potential against PCa.
尽管在诊断和干预方面取得了巨大进展，但激素难治性前列腺癌（HRPC）仍然是前列腺癌（PCa）治疗中的一个主要障碍。代谢重编程在PCa的发生和耐药中起关键作用。然而，代谢与肿瘤发生之间的动态关系尚未完全明确。在此，我们证明两种多靶点天然产物，大麻二酚（CBD）和大麻萜酚（CBG），通过重编程代谢和致癌信号，在小鼠前列腺转基因腺癌（TRAMP）模型中抑制HRPC的发展。从机制上讲，CBD增加了恩杂鲁胺耐药的HRPC细胞的糖酵解能力并抑制氧化磷酸化。CBD的这一作用源于其通过调节线粒体外膜上的电压依赖性阴离子通道1（VDAC1）和己糖激酶II（HKII）偶联对代谢可塑性的影响，这导致线粒体功能和致癌信号通路发生显著变化。CBG对恩杂鲁胺耐药的HRPC细胞的作用不如CBD明显，且仅部分归因于其对线粒体的作用。然而，当这两种大麻素进行最佳组合时，它们在TRAMP小鼠中表现出强大的抗肿瘤作用，即使这些小鼠对恩杂鲁胺已经产生耐药，这表明它们对PCa具有治疗潜力。
