Vitamin D Compounds PRI-2191 and PRI-2205 Enhance Anastrozole Activity in Human Breast Cancer Models

• Published in: International journal of molecular sciences 2021-03, Vol.22 (5), p.2781
• Main Authors: Filip-Psurska, Beata, Psurski, Mateusz, Anisiewicz, Artur, Libako, Patrycja, Zbrojewicz, Ewa, Maciejewska, Magdalena, Chodyński, Michał, Kutner, Andrzej, Wietrzyk, Joanna
• Format: Article
• Language: English
• Subjects: anastrozole; Anastrozole - agonists; Anastrozole - pharmacology; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; aromatase; breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Calcitriol - analogs & derivatives; Calcitriol - pharmacology; Dihydroxycholecalciferols - pharmacology; estrogen receptor; Female; Humans; MCF-7 Cells; Mice; Mice, SCID; vitamin D analog; Xenograft Model Antitumor Assays
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22052781

1,25-Dihydroxycholecalciferol, the hormonally active vitamin D metabolite, is known to exhibit therapeutic effects against breast cancer, mainly by lowering the expression of estrogen receptors and aromatase activity. Previously, the safety of the vitamin D active metabolite (24 )-1,24-dihydroxycholecalciferol (PRI-2191) and 1,25(OH) D analog PRI-2205 was tested, and the in vitro activity of these analogs against different cancer cell lines was studied. We determined the effect of the two vitamin D compounds on anastrozole (An) activity against breast cancer based on antiproliferative activity, ELISA, flow cytometry, enzyme inhibition potency, PCR, and xenograft study. Both the vitamin D active metabolite and synthetic analog regulated the growth of not only estrogen receptor-positive cells (T47D and MCF-7, in vitro and in vivo), but also hormone-independent cancer cells such as SKBR-3 (HER-2-positive) and MDA-MB-231 (triple-negative), despite their relatively low VDR expression. Combined with An, PRI-2191 and PRI-2205 significantly inhibited the tumor growth of MCF-7 cells. Potentiation of the antitumor activity in combined treatment of MCF-7 tumor-bearing mice is related to the reduced activity of aromatase by both An (enzyme inhibition) and vitamin D compounds (switched off/decreased aromatase gene expression, decreased expression of other genes related to estrogen signaling) and by regulation of the expression of the estrogen receptor ERα and VDR.