Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Subdirección de Investigación Básica, Instituto Nacional de Cancerologia, Mexico City, Mexico.
Curr Med Chem. 2024;31(22):3265-3285. doi: 10.2174/0929867330666230607104441.
Prostate cancer is the most frequently diagnosed malignancy in 112 countries and is the leading cause of death in eighteen. In addition to continuing research on prevention and early diagnosis, improving treatments and making them more affordable is imperative. In this sense, the therapeutic repurposing of low-cost and widely available drugs could reduce global mortality from this disease. The malignant metabolic phenotype is becoming increasingly important due to its therapeutic implications. Cancer generally is characterized by hyperactivation of glycolysis, glutaminolysis, and fatty acid synthesis. However, prostate cancer is particularly lipidic; it exhibits increased activity in the pathways for synthesizing fatty acids, cholesterol, and fatty acid oxidation (FAO).
Based on a literature review, we propose the PaSTe regimen (Pantoprazole, Simvastatin, Trimetazidine) as a metabolic therapy for prostate cancer. Pantoprazole and simvastatin inhibit the enzymes fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR), therefore, blocking the synthesis of fatty acids and cholesterol, respectively. In contrast, trimetazidine inhibits the enzyme 3-β-Ketoacyl- CoA thiolase (3-KAT), an enzyme that catalyzes the oxidation of fatty acids (FAO). It is known that the pharmacological or genetic depletion of any of these enzymes has antitumor effects in prostatic cancer.
Based on this information, we hypothesize that the PaSTe regimen will have increased antitumor effects and may impede the metabolic reprogramming shift. Existing knowledge shows that enzyme inhibition occurs at molar concentrations achieved in plasma at standard doses of these drugs.
We conclude that this regimen deserves to be preclinically evaluated because of its clinical potential for the treatment of prostate cancer.
前列腺癌是 112 个国家最常见的恶性肿瘤，也是 18 个国家的主要死因。除了继续研究预防和早期诊断外，改善治疗方法并使其更负担得起至关重要。在这方面，廉价且广泛可用的药物的治疗再利用可以降低这种疾病的全球死亡率。恶性代谢表型因其治疗意义而变得越来越重要。癌症通常表现为糖酵解、谷氨酰胺分解和脂肪酸合成的过度激活。然而，前列腺癌特别具有脂质性；它表现出合成脂肪酸、胆固醇和脂肪酸氧化（FAO）途径的活性增加。
基于文献综述，我们提出 PaSTe 方案（泮托拉唑、辛伐他汀、曲美他嗪）作为前列腺癌的代谢治疗。泮托拉唑和辛伐他汀抑制脂肪酸合酶（FASN）和 3-羟-3-甲基戊二酰辅酶 A 还原酶（HMGCR）的酶，因此分别阻断脂肪酸和胆固醇的合成。相比之下，曲美他嗪抑制酶 3-β-酮酰-辅酶 A 硫解酶（3-KAT），该酶催化脂肪酸的氧化（FAO）。已知这些酶中的任何一种的药理学或遗传耗竭都具有前列腺癌的抗肿瘤作用。
基于此信息，我们假设 PaSTe 方案将具有增强的抗肿瘤作用，并可能阻碍代谢重编程的转变。现有知识表明，在这些药物的标准剂量下，在血浆中达到的摩尔浓度下会发生酶抑制。
我们得出结论，由于其在治疗前列腺癌方面的临床潜力，该方案值得进行临床前评估。
