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

Beata Filip-Psurska,Mateusz Psurski,Magdalena Maciejewska,Andrzej Kutner,Artur Anisiewicz,Ewa Zbrojewicz,Joanna Wietrzyk,Michał Chodyński,Patrycja Libako

doi:10.3390/ijms22052781

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.

Highlights

Breast cancer is the most common cancer among women worldwide and is the leading cause of cancer-related deaths
Many preclinical studies and clinical reports indicate that the addition of vitamin D (D2 or D3) or analogs of 1,25-Dihydroxycholecalciferol (1,25(OH)2D3, calcitriol) (Figure 1) to a breast cancer treatment regimen based on the use of selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs) might improve the efficacy of chemotherapy and ameliorate musculoskeletal symptoms and joint pain in patients
Researchers have suggested that vitamin D3 daily doses at 2000 IU per day or greater may be necessary for postmenopausal women to maintain optimal bone health and that these doses can be safely administered [10,11]. These findings suggest that therapeutic agents that can augment the activity of anastrozole without additional toxicity (e.g., analogs of 1,25(OH)2D3) may be mandatory to improve the activity of AIs and overcome the adverse effects of long-term treatment with AIs

Summary

Introduction

Breast cancer is the most common cancer among women worldwide and is the leading cause of cancer-related deaths. Anastrozole is well-tolerated, its inhibitory activity lacks tissue selectivity, resulting in overall aromatase inhibition in different types of cells expressing this enzyme [1]. Long-term treatment with AIs often results in bone resorption and increased demineralization, an increase in the osteoporosis incidence rate, or more often, bone failure or fracture lesions [2] or AI-associated arthralgia [3]. All these side effects are strongly related to perturbed calcium homeostasis after estrogen depletion

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Conclusion