A Novel Small Molecule Inhibits Tumor Growth and Synergizes Effects of Enzalutamide on Prostate Cancer

Abstract

Prostate cancer (PCa) is the second leading cause of cancerrelated death for men in the United States. Approximately 35% of PCa recurs and is often transformed to castration-resistant prostate cancer (CRPCa), the most deadly and aggressive form of PCa. However, the CRPCa standard-of-care treatment (enzalutamide with abiraterone) usually has limited efficacy. Herein, we report a novel molecule (PAWI-2) that inhibits cellular proliferation of androgen-sensitive and androgen-insensitive cells (LNCaP and PC-3, respectively). In vivo studies in a PC-3 xenograft model showed that PAWI-2 (20 mg/kg per day i.p., 21 days) inhibited tumor growth by 49% compared with vehicletreated mice. PAWI-2 synergized currently clinically used enzalutamide in in vitro inhibition of PCa cell viability and resensitized inhibition of in vivo PC-3 tumor growth. Compared with vehicletreated mice, PC-3 xenograft studies also showed that PAWI-2 (20 mg/kg per day i.p., 21 days) and enzalutamide (5 mg/kg per day i.p., 21 days) inhibited tumor growth by 63%. Synergism was mainly controlled by the imbalance of prosurvival factors (e.g., Bcl-2, Bcl-xL, Mcl-1) and antisurvival factors (e.g., Bax, Bak) induced by affecting mitochondrial membrane potential/ mitochondria dynamics. Thus, PAWI-2 utilizes a distinct mechanism of action to inhibit PCa growth independently of androgen receptor signaling and overcomes enzalutamide-resistant CRPCa. SIGNIFICANCE STATEMENT Castration-resistant prostate cancer (CRPCa) is the most aggressive human prostate cancer (PCa) but standard chemotherapies for CRPCa are largely ineffective. PAWI-2 potently inhibits PCa proliferation in vitro and in vivo regardless of androgen receptor status and uses a distinct mechanism of action. PAWI-2 has greater utility in treating CRPCa than standard-of-care therapy. PAWI-2 possesses promising therapeutic potency in low-dose combination therapy with a clinically used drug (e.g., enzalutamide). This study describes a new approach to address the overarching challenge in clinical treatment of CRPCa.

Hydralazine and Enzalutamide: Synergistic Partners against Prostate Cancer

“…This is an important finding, considering the high mortality rates of prostate cancer due to metastasis development [44]. Regarding the treatment outcome of the single agents, our data confirmed that hydralazine downregulates cell invasion [45], whereas conflicting results were reported regarding enzalutamide, which has been described both as a suppressor [46], as well as a promoter of invasion [47].…”

Bardoxolone-Methyl (CDDO-Me) Suppresses Androgen Receptor and Its Splice-Variant AR-V7 and Enhances Efficacy of Enzalutamide in Prostate Cancer Cells

“…In vitro clonogenic assays simulate the seeding and proliferation of tumor initiating cells, i.e., cancer stem cells [74]. A number of previous studies have already been carried out in tumor xenografts in vivo using either clinically approved ENZ [75][76][77][78][79] or CDDO-Me [26,37,40,41,44] alone; and therefore, studies using the combination of CDDO-Me and ENZ in tumor-bearing mice, would be the next feasible direction of our current findings. Taken together, our in vitro finding suggests a possible benefit of using safe concentrations of CDDO-Me alone to suppress the growth of micro-metastatic foci, and as an adjunct therapy to enhance the efficacy of antiandrogens.…”

PPFIA4 promotes castration-resistant prostate cancer by enhancing mitochondrial metabolism through MTHFD2

“…It has been reported that novel mitochondria-targeted therapeutic agents, like Pentamidine, Atpenin A5, and Urupocidin c could efficiently suppress PCa progression [ 51 – 53 ]. Moreover, PAWI-2 can activate mitochondrial-controlled p53-dependent apoptotic signaling and possesses promising therapeutic potency in low-dose combination therapy with enzalutamide [ 54 , 55 ]. In this study, we identified the PPFIA4-MTHFD2 axis as an important pathway to activate mitochondria metabolism and blocking this pathway by a specific inhibitor DS18561882 towards MTHFD2 could efficiently delay CRPC progression.…”