Kalabay Márton, Szász Zsófia, Láng Orsolya, Lajkó Eszter, Pállinger Éva, Duró Cintia, Jernei Tamás, Csámpai Antal, Takács Angéla, Kőhidai László
Department of Genetics, Cell and Immunobiology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary.
Department of Inorganic Chemistry, Faculty of Chemistry, Eötvös Loránd University, 1053 Budapest, Hungary.
Pharmaceuticals (Basel). 2022 Mar 5;15(3):314. doi: 10.3390/ph15030314.
Tamoxifen is a long-known anti-tumor drug, which is the gold standard therapy in estrogen receptor (ER) positive breast cancer patients. According to previous studies, the conjugation of the original tamoxifen molecule with different functional groups can significantly improve its antitumor effect. The purpose of this research was to uncover the molecular mechanisms behind the cytotoxicity of different ferrocene-linked tamoxifen derivates. Tamoxifen and its ferrocene-linked derivatives, T5 and T15 were tested in PANC1, MCF7, and MDA-MB-231 cells, where the incorporation of the ferrocene group improved the cytotoxicity on all cell lines. PANC1, MCF7, and MDA-MB-231 express ERα and GPER1 (G-protein coupled ER 1). However, ERβ is only expressed by MCF7 and MDA-MB-231 cells. Tamoxifen is a known agonist of GPER1, a receptor that can promote tumor progression. Analysis of the protein expression profile showed that while being cytotoxic, tamoxifen elevated the levels of different tumor growth-promoting factors (e.g., Bcl-XL, Survivin, EGFR, Cathepsins, chemokines). On the other hand, the ferrocene-linked derivates were able to lower these proteins. Further analysis showed that the ferrocene-linked derivatives significantly elevated the cellular oxidative stress compared to tamoxifen treatment. In conclusion, we were able to find two molecules possessing better cytotoxicity compared to their unmodified parent molecule while also being able to counter the negative effects of the presence of the GPER1 through the ER-independent mechanism of oxidative stress induction.
他莫昔芬是一种广为人知的抗肿瘤药物，是雌激素受体（ER）阳性乳腺癌患者的金标准治疗药物。根据以往的研究，将原始他莫昔芬分子与不同官能团结合可显著提高其抗肿瘤效果。本研究的目的是揭示不同二茂铁连接的他莫昔芬衍生物细胞毒性背后的分子机制。在PANC1、MCF7和MDA-MB-231细胞中测试了他莫昔芬及其二茂铁连接的衍生物T5和T15，二茂铁基团的引入提高了对所有细胞系的细胞毒性。PANC1、MCF7和MDA-MB-231表达ERα和GPER1（G蛋白偶联雌激素受体1）。然而，ERβ仅由MCF7和MDA-MB-231细胞表达。他莫昔芬是GPER1的已知激动剂，该受体可促进肿瘤进展。蛋白质表达谱分析表明，他莫昔芬虽然具有细胞毒性，但能提高不同肿瘤生长促进因子（如Bcl-XL、Survivin、表皮生长因子受体、组织蛋白酶、趋化因子）的水平。另一方面，二茂铁连接的衍生物能够降低这些蛋白质的水平。进一步分析表明，与他莫昔芬处理相比，二茂铁连接的衍生物显著提高了细胞氧化应激水平。总之，我们发现了两种分子，它们与其未修饰的母体分子相比具有更好的细胞毒性，同时还能够通过非依赖于雌激素受体的氧化应激诱导机制对抗GPER1存在的负面影响。
