Abstract
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.
Highlights
Progestins are synthetic sex steroid hormones, analogues of progesterone.For decades, progestins have been traditionally used for contraception, maintenance of pregnancy with threatened miscarriage, in hormone replacement therapy, and assisted reproductive technology procedures
We summarized the data on the cytostatic and chemosensitizing effects of different progestins and possible mechanisms of their action, including our data obtained with the newly synthesized pregnane progestin gestobutanoyl, a derivative of 17-acetatemepregenol
It was shown that incubation with 20 μM progesterone significantly decreased the expression level of the NEAT1, miR-146b-5p, LEF1, c-myc, and MMP9 genes of the WNT/β-catenin signaling pathway in Ishikawa endometrial cancer cells, wherein the cell cycle was inhibited in the G0/G1 phase [38]
Summary
Progestins (gestagens) are synthetic sex steroid hormones, analogues of progesterone. The cytostatic and chemosensitizing action of gestagens on different types of cancers, especially hormone-dependent tumors, and their ability to increase the anticancer activity of the classical cytostatics doxorubicin and cisplatin have not yet been clinically studied. Pregnane derivatives have specific effects [9,10] These additional properties can underlie their possible application in the treatment of hormone-dependent tumors. Among all approved progestins, synthetic derivatives of P4, megestrol acetate (MA) and medroxyprogesterone acetate (MPA) have been recommended for use in the treatment of different types of cancers Their effectiveness was confirmed in clinical trials in regard to a complete response rate and pathological remission (Table 2). They are associated with the regulation of ER expression, modulation of proliferative cell signaling, and triggering of mitochondrialdependent apoptosis
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