Shams Shams Ge, Dawud Dalal, Michalak Kasia, Makhlouf Maysoon M, Moustafa Ahmed, Jazwinski S Michal, Kang Lin, Zerfaoui Mourad, El Sayed Khalid A, Abd Elmageed Zakaria Y
Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine (VCOM) Monroe, LA 71203, USA.
Tulane Center for Aging, School of Medicine, Tulane University New Orleans, LA 70112, USA.
Am J Cancer Res. 2024 Dec 15;14(12):5697-5716. doi: 10.62347/XXXA3182. eCollection 2024.
Prostate cancer (PCa) is the second leading cause of cancer-related deaths among American men. The development of metastatic castration resistant PCa (mCRPC) is the current clinical challenge. Antiandrogens such as Enzalutamide (ENZ) are commonly used for CRPC treatment. However, patients with androgen receptor (AR)-negative tumors do not respond to ENZ, while AR-positive tumors frequently develop resistance, limiting the long-term efficacy of this therapy. This study investigates the efficacy of neutral sphingomyelinase 2 (n-SMase2) inhibition by DPTIP, both alone and in combination with ENZ, as a therapeutic strategy for mCRPC. assays were conducted to determine the half-maximal inhibitory concentration (IC) of DPTIP and ENZ in mCRPC cells. The effect of these treatments on cell proliferation, migration, and colony formation was assessed. The antitumor effect of DPTIP was also evaluated in a preclinical PCa mouse model. Elevated n-SMase2 expression was observed in PCa patients compared to normal subjects at both mRNA and protein levels. In CWR-R1ca and PC-3 cells, DPTIP had IC values of 10.31 and 14.57 µM, while ENZ had IC values of 33.7 and 81 µM, respectively. Combined treatment significantly suppressed cell proliferation, colony formation, and migration of mCRPC cells. Mechanistically, the ERK1/2 activity and the expression of nSMase2 and NF-kB p65 were inhibited by DPTIP. The combination of DPTIP and ENZ reduced tumor size and weight more effectively than either drug alone, without significant changes in body weight. This study highlights the therapeutic potential of targeting n-SMase2 for mCRPC. Inhibition of n-SMase2 using DPTIP, both as a standalone treatment and in combination with ENZ, effectively suppressed the growth and migration of mCRPC cells. These findings suggest a promising novel approach to treating mCRPC and warrant further investigation in clinical settings.
前列腺癌（PCa）是美国男性癌症相关死亡的第二大主要原因。转移性去势抵抗性前列腺癌（mCRPC）的发展是当前的临床挑战。恩杂鲁胺（ENZ）等抗雄激素药物常用于CRPC治疗。然而，雄激素受体（AR）阴性肿瘤患者对ENZ无反应，而AR阳性肿瘤则经常产生耐药性，限制了该疗法的长期疗效。本研究调查了DPTIP单独及与ENZ联合抑制中性鞘磷脂酶2（n-SMase2）作为mCRPC治疗策略的疗效。进行实验以确定DPTIP和ENZ在mCRPC细胞中的半数最大抑制浓度（IC）。评估了这些处理对细胞增殖、迁移和集落形成的影响。还在临床前PCa小鼠模型中评估了DPTIP的抗肿瘤作用。与正常受试者相比，在mRNA和蛋白质水平上均观察到PCa患者中n-SMase2表达升高。在CWR-R1ca和PC-3细胞中，DPTIP的IC值分别为10.31和14.57 µM，而ENZ的IC值分别为33.7和81 µM。联合治疗显著抑制了mCRPC细胞的增殖、集落形成和迁移。从机制上讲，DPTIP抑制了ERK1/2活性以及nSMase2和NF-κB p⁶⁵的表达。DPTIP与ENZ联合使用比单独使用任何一种药物更有效地减小了肿瘤大小和重量，且体重无显著变化。本研究突出了靶向n-SMase2治疗mCRPC的治疗潜力。使用DPTIP抑制n-SMase2，无论是作为单独治疗还是与ENZ联合使用，均有效抑制了mCRPC细胞的生长和迁移。这些发现提示了一种有前景的治疗mCRPC的新方法，值得在临床环境中进一步研究。
