Novel Strategy of Proxalutamide for the Treatment of Prostate Cancer through Coordinated Blockade of Lipogenesis and Androgen Receptor Axis

Abstract

Objective: Prostate cancer (PCa) is the most common malignant tumor diagnosed in men in developed countries. In developing countries, the PCa morbidity and mortality rates are also increasing rapidly. Since androgen receptor (AR) is a key driver and plays a critical role in the regulation of PCa development, AR-targeted agents provide a key component of current therapy regimens. However, even new-generation AR antagonists are prone to drug resistance, and there is currently no effective strategy for overcoming advanced PCa aggressiveness, including drug-resistance progression. The aim of this study was to evaluate the potential efficacy and novel therapy strategy of proxalutamide (a newly developed AR antagonist) in PCa. Methods: Four PCa cell lines with various biological heterogeneities were utilized in this study, namely, androgen-sensitive/-insensitive with/without AR expression. Proliferation, migration and apoptosis assays in PCa cells were used to evaluate the effective therapeutic activity of proxalutamide. The changes in lipid droplet accumulation and lipidomic profiles were analyzed to determine the influence of proxalutamide on lipogenesis in PCa cells. The molecular basis of the effects of proxalutamide on lipogenesis and the AR axis was then further investigated. Results: Proxalutamide significantly inhibited the proliferation and migration of PCa cells, and its inhibitory effect was superior to that of enzalutamide (Enz, second-generation AR antagonist). Proxalutamide induced the caspase-dependent apoptosis of PCa cells. Proxalutamide significantly diminished the level of lipid droplets in PCa cells, changed the lipid profile of PCa cells and reduced the content of most lipids (especially triglycerides) in PCa cells. Proxalutamide attenuated de novo lipogenesis by inhibiting the expression of ATP citrate lyase (ACL), acetyl CoA carboxylase (ACC), fatty acid synthase (FASN) and sterol regulatory element-binding protein-1 (SREBP-1). Moreover, proxalutamide also decreased AR expression in PCa cells, and its inhibitory effect on lipogenesis did not depend on its ability to down-regulate AR expression. However, Enz had no effect on AR expression, lipid accumulation or lipid de novo synthesis in PCa cells. Conclusions: By co-targeting the AR axis and endogenous adipogenesis, a novel and promising strategy was established for proxalutamide to combat the progress of PCa. The unique effect of proxalutamide on the metabolic reprogramming of PCa provides a potential solution to overcome the resistance of current AR-targeted therapy, which will help to effectively prolong its clinical service life.

Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer

“…A newly developed AR antagonist, proxalutamide, significantly inhibits proliferation and migration, induces the caspase-dependent apoptosis, and diminishes the level of lipid droplets in PCa cells by regulating the levels of ACL, ACC, FASN, and SREBP-1. Moreover, proxalutamide can decrease AR expression in PCa cells, which may overcome the resistance of AR-targeted therapy ( 147 ). Leelamine, a pyruvate dehydrogenase kinase inhibitor, can downregulate the expressions of SREBP-1 and key fatty acid synthesis enzymes (ACLY, ACC1, FASN) at the mRNA and protein levels to suppress fatty acid synthesis against PCa progression ( 148 ).…”

Cheminformatic Analysis and Machine Learning Modeling to Investigate Androgen Receptor Antagonists to Combat Prostate Cancer

“…Phase II clinical trial (clinical trial information: NCT03899467) for mCRPC patients in the United States is expected to be complete by the end of 2022. It is revealed that GT-0918 as an orally available novel candidate drug acts not only by antagonizing AR but also by downregulating the lipogenesis through inhibiting the expression of ATP citrate lyase (ACL), acetyl CoA carboxylase (ACC), fatty acid synthase (FASN), and sterol regulatory element-binding protein-1 (SREBP-1). , The coinhibition of AR signaling pathway and lipogenesis process confers GT-0918 more promising prospectus to overcome drug resistance and benefit patients’ survival. TRC-253, known as JNJ-63576253, is a novel, orally available novel candidate drug that has completed phase II/A clinical trial in Nov, 2020 .…”

“…At the moment of this study, there are some novel AR antagonist candidates that have already proceeded to phase I/II clinical trials. Proxalutamide, also known as GT-0918, which shares the same scaffold with second-generation antagonists, has passed phase I clinical trial (clinical trial information: NCT02826772) with a 3-fold more potent binding affinity than enzalutamide and satisfactory tolerance . Phase II clinical trial (clinical trial information: NCT03899467) for mCRPC patients in the United States is expected to be complete by the end of 2022.…”

“…Proxalutamide, also known as GT-0918, which shares the same scaffold with second-generation antagonists, has passed phase I clinical trial (clinical trial information: NCT02826772) with a 3-fold more potent binding affinity than enzalutamide and satisfactory tolerance. 28 Phase II clinical trial (clinical trial information: NCT03899467) for mCRPC patients in the United States is expected to be complete by the end of 2022. It is revealed that GT-0918 as an orally available novel candidate drug acts not only by antagonizing AR but also by downregulating the lipogenesis through inhibiting the expression of ATP citrate lyase (ACL), acetyl CoA carboxylase (ACC), fatty acid synthase (FASN), and sterol regulatory element-binding protein-1 (SREBP-1).…”

Chaihu-Shugan-San ameliorates tumor growth in prostate cancer promoted by depression via modulating sphingolipid and glycerinphospholipid metabolism

“…Emerging evidence suggests that lipid metabolism is involved in psychologic depression or chronic stress through glucocorticoid pathway and inflammatory pathway ( Zhou et al, 2019 ; Xie et al, 2020 ; Borsini et al, 2021 ). Disordered lipid metabolism is a notable feature of PCa that is driven by androgen receptor (AR) signaling ( Zadra et al, 2019 ; Gu et al, 2021 ; Zhou et al, 2021 ). In clinical PCa, lipidomic analysis revealed higher proportions of monounsaturated phosphatidylinositol (PI) and phosphatidylserine (PS) in tumors.…”