Antiproliferative effects of 13α/β-steroids on triple-negative MDA-MB-231 breast cancer cells: unraveling intracellular signaling without ERα

Alexander Scherbakov; Yury  Kuznetsov; Margarita Yastrebova; Alvina Khamidullina; Danila Sorokin; Maria Tserfas; Inna Levina

doi:10.1590/s2175-97902023e22540

Authors

Alexander Scherbakov N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye Shosse 24, Moscow 115522, Russia https://orcid.org/0000-0002-2974-9555
Yury Kuznetsov N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia
Margarita Yastrebova Laboratory of Molecular Oncobiology, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Vavilova st. 34/5, Moscow 119334, Russia
Alvina Khamidullina Laboratory of Molecular Oncobiology, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Vavilova st. 34/5, Moscow 119334, Russia
Danila Sorokin N.N. Blokhin National Medical Research Center of Oncology, Kashirskoye Shosse 24, Moscow 115522, Russia
Maria Tserfas N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia
Inna Levina 2 N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia

DOI:

https://doi.org/10.1590/s2175-97902023e22540

Keywords:

Breast cancer, Steroids, GLUT1, Metformin, Apoptosis

Abstract

This study aimed to investigate the activities of novel 20(R)-3,20-dihydroxy-19-norpregn-1,3,5(10)-trienes (kuz7 and kuz8b) of natural 13β- and epimeric 13α-series against triple-negative MDA-MB-231 breast cancer cells. High antiproliferative activity of synthesized compounds kuz8b and kuz7 against MDA-MB-231 triple-negative cancer cells was revealed. The steroid kuz7 of natural 13β-configuration was more active against MDA-MB-231 cells than the 13α-steroid kuz8b. Cell cycle analysis revealed common patterns for the action of both tested compounds. The number of cells in the subG1 phase increased in a dose-dependent manner, indicating induction of apoptosis, which was also verified by PARP cleavage. In contrast, the number of cells in the G0/G1 phase decreases with increasing compound concentration. Steroid kuz7 at micromolar concentrations reduced the expression of GLUT1, a glucose transporter. High efficacy of the combination of kuz7 with biguanide metformin was shown, and synergistic effects on MDA-MB-231 cell growth and expression of the anti-apoptotic protein Bcl-2 were revealed. According to the obtained results, including the high activity of kuz7 against triple-negative cancer cells, the detected induction of apoptosis, and the decrease in GLUT1 expression, 13β-steroid kuz7 is of interest for further preclinical studies both alone and in combination with the metabolic drug metformin.

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