Progestins as Anticancer Drugs and Chemosensitizers, New Targets and Applications

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.

Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

“…In fibrosis, TGFβ blockade suppresses epithelial–mesenchymal transition, inhibits fibroblast differentiation and proliferation, and prevents excessive elaboration of the extracellular matrix [ 89 ]. In turn, P 4 inhibits TGFβ production [ 90 ]. Accordingly, P 4 and progestins decrease the expression of TGFβ target genes SMAD, P38, NFKBP, RAS, and PI3K [ 91 ].…”

Linarin, a Glycosylated Flavonoid, with Potential Therapeutic Attributes: A Comprehensive Review

“…Cancer is one of the major causes of death worldwide, affecting more than 14.1 million people worldwide [111]. Over the past few years, attention has been paid to find potent natural products as anticancer therapeutic agents [79,112,113].…”

The Role of Autophagy and Apoptosis in the Combined Action of Plasma-Treated Saline, Doxorubicin, and Medroxyprogesterone Acetate on K562 Myeloid Leukaemia Cells

“…Progestins have also shown anti-tumour effects on cells having receptors for progesterone or glucocorticoids [ 33 , 34 , 35 ]. Medroxyprogesterone acetate (MPA) have been successfully used to treat advanced breast cancer, endometrial cancer, prostate cancer, and endometrial hyperplasia [ 36 ]. Since the cytotoxic effect of MPA on tumour cells occur through interaction with specific receptors, its use for the treatment of oncological diseases looks attractive.…”