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

Abstract

1,25-Dihydroxycholecalciferol, the hormonally active vitamin D3 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 (24R)-1,24-dihydroxycholecalciferol (PRI-2191) and 1,25(OH)2D3 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.

Vitamin D, Th17 Lymphocytes, and Breast Cancer

“…Thus, combined use of calcitriol with one of three different AIs, namely exemestane, letrozole, or anastrozole, caused enhanced inhibition of MCF-7 cell growth [ 146 ]. Our studies confirmed these findings in human MCF-7 xenografted mice demonstrating tumor growth inhibition after treatment with new vitamin D analogs, PRI-2191 and PRI-2205, either alone or in combination with anastrozole [ 147 ]. In addition, Swami et al revealed that calcitriol acted as a selective aromatase modulator in mice, decreasing aromatase expression in the mammary adipose tissue and increasing it in bone marrow cells, but not altering the enzyme expression in the ovaries and uteri [ 148 ].…”

Targeting nuclear hormone receptors for the prevention of breast cancer

“…More recently, it has been demonstrated that retinoids can block PR binding at shared DNA response element regions and inhibit P4 stimulated growth of ER-positive breast cancer xenografts, suggesting a cross-talk between PR and RAR in regulating a subset of hormone responsive breast cancer ( 188 ). It has also been shown that the addition of vitamin D analogs could potentiate the antitumor effect of the AI anastrozole in MCF7 tumor bearing mice via regulation of both VDR and ER signaling ( 189 ). In addition, VDR activation, with vitamin D or the synthetic analogue EB1089, could re-sensitize an antiestrogen resistant MCF7 breast cancer cell line to tamoxifen treatment and reduce the incidence of ER-positive mammary tumors in a preclinical model ( 190 ).…”

Combinations of Calcitriol with Anticancer Treatments for Breast Cancer: An Update

“…Another study has demonstrated that the VD active metabolite (24R)1,24-dihydroxycholecalciferol (PRI-2191) and the analog PRI-2205 significantly enhanced the antitumor activity of anastrozole in BC tumors and cells [ 155 ].…”