Mendrina Theresa, Poetsch Isabella, Schueffl Hemma, Baier Dina, Pirker Christine, Ries Alexander, Keppler Bernhard K, Kowol Christian R, Gibson Dan, Grusch Michael, Berger Walter, Heffeter Petra
Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Faculty of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
Pharmaceutics. 2023 Feb 16;15(2):677. doi: 10.3390/pharmaceutics15020677.
For a variety of cancer types, platinum compounds are still among the best treatment options. However, their application is limited by side effects and drug resistance. Consequently, multi-targeted platinum(IV) prodrugs that target specific traits of the malignant tissue are interesting new candidates. Recently, cisPt(PhB) was synthesized which, upon reduction in the malignant tissue, releases phenylbutyrate (PhB), a metabolically active fatty acid analog, in addition to cisplatin. In this study, we in-depth investigated the anticancer properties of this new complex in cell culture and in mouse allograft experiments. CisPt(PhB) showed a distinctly improved anticancer activity compared to cisplatin as well as to PhB alone and was able to overcome various frequently occurring drug resistance mechanisms. Furthermore, we observed that differences in the cellular fatty acid metabolism and mitochondrial activity distinctly impacted the drug's mode of action. Subsequent analyses revealed that "Warburg-like" cells, which are characterized by deficient mitochondrial function and fatty acid catabolism, are less capable of coping with cisPt(PhB) leading to rapid induction of a non-apoptotic form of cell death. Summarizing, cisPt(PhB) is a new orally applicable platinum(IV) prodrug with promising activity especially against cisplatin-resistant cancer cells with "Warburg-like" properties.
对于多种癌症类型而言，铂类化合物仍是最佳治疗选择之一。然而，它们的应用受到副作用和耐药性的限制。因此，靶向恶性组织特定特征的多靶点铂（IV）前药成为了有趣的新候选药物。最近，合成了顺铂（PhB），其在恶性组织中还原后，除了释放顺铂外，还会释放苯丁酸盐（PhB），一种具有代谢活性的脂肪酸类似物。在本研究中，我们在细胞培养和小鼠异种移植实验中深入研究了这种新复合物的抗癌特性。与顺铂以及单独的PhB相比，顺铂（PhB）显示出明显增强的抗癌活性，并且能够克服各种常见的耐药机制。此外，我们观察到细胞脂肪酸代谢和线粒体活性的差异显著影响了药物的作用方式。随后的分析表明，以线粒体功能和脂肪酸分解代谢缺陷为特征的“类瓦伯格”细胞应对顺铂（PhB）的能力较弱，导致快速诱导非凋亡形式的细胞死亡。总之，顺铂（PhB）是一种新型口服铂（IV）前药，具有良好的活性，尤其对具有“类瓦伯格”特性的顺铂耐药癌细胞有效。
