Breast cancer is the most common cancer in women. There is an urgent need for new drugs with novel modes of effect on tumors. It is very important to develop compounds with high activity against tumor cells and low toxicity on normal epithelium. The development of new anti-tumor drugs based on steroidal compounds is a promising approach for obtaining agents that combine antiestrogenic, cytostatic and proapoptotic effects. The aim of the work is to study the mechanism of anticancer action of new steroidal compound, 3,20 (R)-dihydroxy-19-norpregnatriene (Kuz7).
MCF-7 breast cancer cell line and MCF-10A human mammary epithelial cell line were obtained from the ATCC collection. Antiproliferative activity was measured by MTT. ERα activity was assessed by gene-reporter assay. Protein expression was measured by standard immunoblotting.
We have developed a new type of anticancer steroids - a series of 3-hydroxyestra-1,3,5(10)-trienes of natural and epimeric 13α-configuration with 17th-side chain bearing the second hydroxy group and 16,17-fused three- or six-membered carbocycle (or without it). Most of these compounds exhibited cytotoxic and ERα inhibiting activities on MCF-7 cells and have low toxicity in the MCF-10A normal epithelial cells. 3,20(R)-dihydroxy-19-norpregnatriene (Kuz7) was selected as a leader molecule for in-depth study. At low doses, Kuz7 caused significant accumulation of p21 and inhibition of CDK2 and CDK4 in MCF-7 cells. Apoptosis provoked by Kuz7 was determined by fragmented PARP. Compound kuz7 is considered as an effective inhibitor of proliferation and ERα signaling in MCF-7 cells. kuz7 decreased cyclin D1 expression and caused cell arrest in G0 phase.
New series of highly active antitumor steroids has been developed. The lead compound, kuz7, blocks the growth of MCF-7 cells through induction of apoptosis and regulation of hormonal pathways and cell cycle. Further studies, in vitro and in vivo, are needed to confirm our findings in relation to luminal type A breast cancer. The work was supported by RFBR (project 19-03-00246).
The authors.
Russian Foundation for Basic Research (project 19-03-00246).
All authors have declared no conflicts of interest.