Ulchenko Darya, Miloykovich Lilia, Zemlyanaya Olga, Shimanovsky Nikolay, Fedotcheva Tatiana
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.
Pharmaceutics. 2023 Dec 16;15(12):2787. doi: 10.3390/pharmaceutics15122787.
A comparative analysis of the cytostatic effects of progestins (gestobutanoyl, megestrol acetate, amol, dienogest, and medroxyprogesterone acetate), glucocorticoids (hydrocortisone, dexamethasone), and diclofenac on tumor cells was carried out in order to confirm their in silico predicted probabilities experimentally. The results showed the different sensitivity of HeLa, MCF-7, Hep-2, K-562, and Wi-38 cell lines to progestins, glucocorticoids, and diclofenac. The minimum IC was found for progestin gestobutanoyl (GB) as 18 µM for HeLa cells, and varied from 31 to 38 µM for MCF-7, Hep-2, and K-562. Glucocorticoids and diclofenac were much less cytotoxic in the HeLa, MCF-7, and Hep-2 cell lines than progestins, with IC values in the range of 150-3000 μM. Myelogenous leukemia K-562 cells were the least sensitive to the action of progestins and glucocorticoids but the most sensitive to diclofenac, which showed a pronounced cytotoxic effect with an IC of 31 μM. As we have shown earlier, progestins can uniquely modulate MPTP opening via the binding of adenine nucleotide translocase. On this basis, we evaluated the expression of adenylate nucleotide translocase ANT1 () as a possible participant in cytotoxic action in these cell lines after 48 h incubation with drugs. The results showed that progestins differently regulated ANT1 expression in different cell lines. Gestobutanoyl had the opposite effect on ANT1 expression in the HeLa, K562, and Wi-38 cells compared with the other progestins. It increased the ANT1 expression more than twofold in the HeLa and K562 cells but had no influence on the Wi-38 cells. Glucocorticoids and diclofenac increased ANT1 expression in the Wi-38 cells and decreased it in the K562, MCF-7, and Hep-2 cells. The modulation of ANT1 expression discovered in our study can be a new explanation of the cytotoxic and cytoprotective effects of hormones, which can vary depending on the cell type. ANT isoforms in normal and cancerous cells could be a new target for steroid hormone and anti-inflammatory drug action.
为了通过实验证实孕激素（孕诺酮丁酰酯、醋酸甲地孕酮、阿摩尔、地诺孕素和醋酸甲羟孕酮）、糖皮质激素（氢化可的松、地塞米松）和双氯芬酸对肿瘤细胞的细胞抑制作用，进行了一项对比分析。结果显示，HeLa、MCF-7、Hep-2、K-562和Wi-38细胞系对孕激素、糖皮质激素和双氯芬酸具有不同的敏感性。发现孕激素孕诺酮丁酰酯（GB）对HeLa细胞的最小半数抑制浓度（IC）为18 μM，对MCF-7、Hep-2和K-562细胞的最小半数抑制浓度在31至38 μM之间。在HeLa、MCF-7和Hep-2细胞系中，糖皮质激素和双氯芬酸的细胞毒性远低于孕激素，其半数抑制浓度值在150 - 3000 μM范围内。髓性白血病K-562细胞对孕激素和糖皮质激素的作用最不敏感，但对双氯芬酸最敏感，双氯芬酸在半数抑制浓度为31 μM时显示出明显的细胞毒性作用。正如我们之前所表明的，孕激素可以通过与腺嘌呤核苷酸转位酶结合独特地调节线粒体通透性转换孔（MPTP）的开放。在此基础上，我们评估了在与药物孵育48小时后，作为这些细胞系细胞毒性作用可能参与者的腺苷酸转位酶ANT1（）的表达。结果表明，孕激素在不同细胞系中对ANT1表达的调节方式不同。与其他孕激素相比，孕诺酮丁酰酯对HeLa、K562和Wi-38细胞中ANT1的表达有相反的影响。它使HeLa和K562细胞中的ANT1表达增加了两倍多，但对Wi-38细胞没有影响。糖皮质激素和双氯芬酸使Wi-38细胞中的ANT1表达增加，而使K562、MCF-7和Hep-2细胞中的ANT1表达降低。我们研究中发现的ANT1表达调节可能是对激素细胞毒性和细胞保护作用的一种新解释，其作用可能因细胞类型而异。正常细胞和癌细胞中的ANT同工型可能是甾体激素和抗炎药物作用的新靶点。
