Vitamin D3 Inhibits the Viability of Breast Cancer Cells In Vitro and Ehrlich Ascites Carcinomas in Mice by Promoting Apoptosis and Cell Cycle Arrest and by Impeding Tumor Angiogenesis

Simple Summary The burden of breast cancer has been increasing at an alarming rate. Epidemiological and empirical evidence has shown the key roles of vitamin D in the mitigation of tumor burden. But, the mechanisms by which vitamin D induces tumor reduction are poorly understood. Therefore, in the current study, we have aimed at understanding the role of vitamin D in inhibiting breast cancer progression in in vitro and in vivo models. The results of this study showed that vitamin D inhibited the proliferation of breast cancer cell lines in vitro and retarded Ehrlich ascites carcinomas in mice by inducing apoptosis as well as by halting cell cycle progression and angiogenesis. Future studies should focus more on strategies to improve the therapeutic index and the retention of vitamin D in tumor cells for better and long-lasting treatment.Abstract The incidence of aggressive and resistant breast cancers is growing at alarming rates, indicating a necessity to develop better treatment strategies. Recent epidemiological and preclinical studies detected low serum levels of vitamin D in cancer patients, suggesting that vitamin D may be effective in mitigating the cancer burden. However, the molecular mechanisms of vitamin D3 (cholecalciferol, vit-D3)-induced cancer cell death are not fully elucidated. The vit-D3 efficacy of cell death activation was assessed using breast carcinoma cell lines in vitro and a widely used Ehrlich ascites carcinoma (EAC) breast cancer model in vivo in Swiss albino mice. Both estrogen receptor-positive (ER+, MCF-7) and -negative (ER-, MDA-MB-231, and MDA-MB-468) cell lines absorbed about 50% of vit-D3 in vitro over 48 h of incubation. The absorbed vit-D3 retarded the breast cancer cell proliferation in a dose-dependent manner with IC50 values ranging from 0.10 to 0.35 mM. Prolonged treatment (up to 72 h) did not enhance vit-D3 anti-proliferative efficacy. Vit-D3-induced cell growth arrest was mediated by the upregulation of p53 and the downregulation of cyclin-D1 and Bcl2 expression levels. Vit-D3 retarded cell migration and inhibited blood vessel growth in vitro as well as in a chorioallantoic membrane (CAM) assay. The intraperitoneal administration of vit-D3 inhibited solid tumor growth and reduced body weight gain, as assessed in mice using a liquid tumor model. In summary, vit-D3 cytotoxic effects in breast cancer cell lines in vitro and an EAC model in vivo were associated with growth inhibition, the induction of apoptosis, cell cycle arrest, and the impediment of angiogenic processes. The generated data warrant further studies on vit-D3 anti-cancer therapeutic applications.

Automated summary

The burden of breast cancer is increasing rapidly, and it is important to develop better treatment strategies. Recent studies have found that low levels of vitamin D may be effective in reducing the cancer burden. However, the molecular mechanisms by which vitamin D induces cancer cell death are not fully understood. This study showed that vitamin D inhibited the proliferation of breast cancer cell lines in vitro and slowed down the growth of breast cancer in mice. The cytotoxic effects of vitamin D were associated with growth inhibition, induction of apoptosis, cell cycle arrest, and inhibition of angiogenesis.