Irrera Pietro, Roberto Miriam, Consolino Lorena, Anemone Annasofia, Villano Daisy, Navarro-Tableros Victor, Carella Antonella, Dastrù Walter, Aime Silvio, Longo Dario Livio
Department of Environmental Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy.
Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), 10126 Turin, Italy.
Metabolites. 2022 Dec 28;13(1):48. doi: 10.3390/metabo13010048.
Novel anticancer treatments target the pH regulating system that plays a major role in tumor progression by creating an acidic microenvironment, although few studies have addressed their effect on tumor acidosis. In this study, we investigated in vivo several proton pump inhibitors (PPIs) targeting NHE-1 (Amiloride and Cariporide) and V-ATPase (Esomeprazole and Lansoprazole) proton transporters in the DU145 androgen-insensitive human prostate cancer model. In cellulo results showed that DU145 are sensitive, with decreasing efficacy, to Amiloride, Esomeprazole and Lansoprazole, with marked cell toxicity both in normoxia and in hypoxia, with almost any change in pH. In vivo studies were performed upon administration of Esomeprazole to assess both the acute and chronic effects, and Iopamidol-based tumor pH imaging was performed to evaluate tumor acidosis. Although statistically significant tumor pH changes were observed a few hours after Esomeprazole administration in both the acute study and up to one week of treatment in the chronic study, longer treatment resulted in a lack of changes in tumor acidosis, which was associated to similar tumor growth curves between treated and control groups in both the subcutaneous and orthotopic models. Overall, this study highlights MRI-CEST tumor pH imaging as a valid approach to monitoring treatment response to PPIs.
新型抗癌治疗方法针对的是pH调节系统，该系统通过营造酸性微环境在肿瘤进展中发挥主要作用，不过很少有研究探讨过其对肿瘤酸中毒的影响。在本研究中，我们在DU145雄激素不敏感型人前列腺癌模型中对几种靶向NHE-1（氨氯吡脒和卡立泊来德）和V-ATP酶（埃索美拉唑和兰索拉唑）质子转运体的质子泵抑制剂（PPIs）进行了体内研究。细胞实验结果显示，DU145细胞对氨氯吡脒、埃索美拉唑和兰索拉唑敏感，但敏感性逐渐降低，在常氧和低氧条件下均有明显的细胞毒性，且pH值几乎没有变化。我们对埃索美拉唑进行了体内给药研究，以评估其急性和慢性效应，并采用基于碘帕醇的肿瘤pH成像来评估肿瘤酸中毒情况。虽然在急性研究中，埃索美拉唑给药后数小时以及慢性研究中长达一周的治疗后均观察到肿瘤pH值有统计学意义的变化，但更长时间的治疗导致肿瘤酸中毒没有变化，这与皮下和原位模型中治疗组与对照组相似的肿瘤生长曲线相关。总体而言，本研究强调MRI-CEST肿瘤pH成像作为监测PPIs治疗反应的有效方法。
