Fedotcheva Tatiana A, Fedotcheva Nadezhda I, Shimanovsky Nikolai L
Science Research Laboratory of Molecular Pharmacology, Medical Biological Faculty, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Ostrovityanova St. 1, 117997 Moscow, Russia.
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya str., 3, Pushchino, 142290 Moscow, Russia.
Pharmaceutics. 2021 Oct 4;13(10):1616. doi: 10.3390/pharmaceutics13101616.
Progesterone and its synthetic analogues, progestins, participate in the regulation of cell differentiation, proliferation and cell cycle progression. Progestins are usually applied for contraception, maintenance of pregnancy, and hormone replacement therapy. Recently, their effectiveness in the treatment of hormone-sensitive tumors was revealed. According to current data, the anticancer activity of progestins is mainly mediated by their cytotoxic and chemosensitizing influence on different cancer cells. In connection with the detection of previously unknown targets of the progestin action, which include the membrane-associated progesterone receptor (PR), non-specific transporters related to the multidrug resistance (MDR) and mitochondrial permeability transition pore (MPTP), and checkpoints of different signaling pathways, new aspects of their application have emerged. It is likely that the favorable influence of progestins is predominantly associated with the modulation of expression and activity of MDR-related proteins, the inhibition of survival signaling pathways, especially TGF-β and Wnt/β-catenin pathways, which activate the proliferation and promote MDR in cancer cells, and the facilitation of mitochondrial-dependent apoptosis. Biological effects of progestins are mediated by the inhibition of these signaling pathways, as well as the direct interaction with the nucleotide-binding domain of ABC-transporters and mitochondrial adenylate translocase as an MPTP component. In these ways, progestins can restore the proliferative balance, the ability for apoptosis, and chemosensitivity to drugs, which is especially important for hormone-dependent tumors associated with estrogen stress, epithelial-to-mesenchymal transition, and drug resistance.
孕酮及其合成类似物孕激素参与细胞分化、增殖和细胞周期进程的调节。孕激素通常用于避孕、维持妊娠及激素替代疗法。最近，其在激素敏感性肿瘤治疗中的有效性得以显现。根据现有数据，孕激素的抗癌活性主要通过其对不同癌细胞的细胞毒性和化学增敏作用介导。随着孕激素作用的先前未知靶点的发现，其中包括膜相关孕酮受体（PR）、与多药耐药性（MDR）相关的非特异性转运蛋白和线粒体通透性转换孔（MPTP）以及不同信号通路的检查点，其应用出现了新的方面。孕激素的有利影响可能主要与MDR相关蛋白的表达和活性调节、生存信号通路的抑制有关，尤其是TGF-β和Wnt/β-连环蛋白通路，这些通路激活癌细胞增殖并促进多药耐药，以及促进线粒体依赖性凋亡。孕激素的生物学效应通过抑制这些信号通路以及与ABC转运蛋白的核苷酸结合结构域和作为MPTP组分的线粒体腺苷酸转位酶直接相互作用来介导。通过这些方式，孕激素可以恢复增殖平衡、凋亡能力和对药物的化学敏感性，这对于与雌激素应激、上皮-间质转化和耐药相关的激素依赖性肿瘤尤为重要。
