Cytostatic Activity and Ligand-Receptor Interaction Energy of the Novel Russian-Produced Gestagen Gestobutanoil and its Metabolites

Pharmaceutical Chemistry Journal - With the aim of clarifying the cytostatic effect of the Russian-made gestagen gestobutanoil (17α-acetoxy-3β-hydroxy-6-methylpregna-4,6-dien-20-one butyl...     

Combined effect of bis-β-chloroethylamine estrogen derivatives and doxorubicin on proliferation of sensitive and resistant MCF-7 cells

The sensitivity of normal (MCF-7/WT) and doxorubicin-resistant (MCF-7/R) breast cancer cells to the antiproliferative effect of ethynylestradiol 11α-derivatives with the cytostatic residue in the 3-position of the steroid ring (antiestrogen cytostatics) was studied by evaluating cell viability using methylthiazole tetrazolium staining. The antiproliferative effects of these agents on cell lines in the presence of doxorubicin were compared. Antiestrogen cytostatics produced weaker cytostatic effect on MCF-7/WT cells, but more potent cytostatic effect on MCF-7/WT cells compared to those of doxorubicin. Moreover, administration of these agents in combination with doxorubicin more significantly suppressed proliferation of tumor cells. Accumulation and efflux of cytostatic doxorubicin in MCF-7/R cells were studied in the presence and absence of antiestrogen cytostatic Po716. Confocal laser microscopy showed that doxorubicin accumulation in MCF-7/R cells in the absence of Po716 took 20 min, while in the presence of antiestrogen cytostatic this process took 5 min. The rate of doxorubicin transport from tumor cells was much lower in the presence of the test antiestrogen cytostatic. Our results suggest that antiestrogen cytostatics increase the sensitivity of resistant MCF-7/R cells to doxorubicin by modulating the mechanisms of multidrug resistance of tumor cells. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 3, pp. 305–307, March, 2007     

Molecular mechanisms of cytostatic and chemosensitizing action of gestagens

In this study cytostatic and chemosensitizing actions of gestagens are described. Cytostatic mechanisms can be divided into estrogen-mediated and independent ones. The former include down-regulation of estrogen receptors, induction of 17?-hydroxysteroid dehydrogenase and estron sulfotransferase. The latter are MAP-kinase inhibition, induction of cell differentiation and apoptosis. Chemosensitization by gestagens is due to inhibition of P-glycoprotein, GST and MRP. Another putative chemosensitization mechanisms involves mitochondrial transition pore (MTP), at least for such gestagens as buterol and acetomepregenol. Elucidation of common mechanisms of MTP and MDR regulation and the possible role of MTP in chemosensitization is a new direction of investigations into the action of steroid hormones.