Radiosensitization of breast cancer cells by Vitamin D3 and Vitamin D analogs

Last updated: May 13, 2010
American Association for Cancer Research (AACR) Meeting, April 2010

http://foodforbreastcancer.com/news/vitamin-d3-sensitizes-breast-cancer-to-radiation-treatment%2c-increasing-cancer-cell-death

A new study recently presented at the annual American Association for Cancer Research (AACR) Meeting in Washington, D.C. has reported that vitamin D3 can enhance sensitivity to radiation treatment in breast cancer cells, thereby increasing the proportion of breast cancer cells killed by radiation. Previous studies conducted by the authors demonstrated that the active form of vitamin D, 1,25-di hydroxy vitamin D3 (D3), or its analogs such as EB 1089, can confer enhanced sensitivity to ionizing radiation. (The vitamin D3 sold to consumers in supplement form is cholecalciferol, which is metabolized in the human body to calcitriol, otherwise known as 1,25-di hydroxy vitamin D3.) The present study was designed to extend the previous findings to ZR-75-1 breast cancer cells (a p53 wild type ER positive cell line) using D3 combined with ionizing radiation.

The effects of D3 alone, ionizing radiation delivered over a period of 3 days, and D3 administered 72 hours prior to radiation treatment were evaluated. Radiation alone was found to reduce total cell number by approximately 30%. Pretreatment with D3 enhanced radiation sensitivity, so that the combination reduced total cell number by approximately 75%. Cell death was followed by a prolonged period of growth arrest under either ionizing radiation treatment alone or ionizing radiation preceded by D3. Surviving cells were in a state of senescence after having undergone either regimen. Taken together with the authors' previous work, the results support the theory that D3 or its analogs enhance radiation sensitivity in breast cancer cells through the promotion of multiple cell death pathways.

Comments regarding the study

The authors attempt to uncover the mechanism of action by which cancer cell death occurred in the study. They provide evidence that the cell death was not normal apoptosis in cells treated either with ionizing radiation alone or pretreated with D3. They also reject autophagy, a type of cell self-digestion which can lead to cell death, as responsible for radiation sensitization in this experiment. In fact, they speculate that autophagy may prove to be cytoprotective instead of cytotoxic and could be involved in regulating senescence. They note that the addition of vitamin D markedly increased the formation of cells with small, double nuclei, which is indicative of mitotic catastrophe.

Vitamin D has been shown to influence the expression of breast cancer-related gene activity, including cell differentiation, cell growth, and angiogenesis, all of which are related to cancer development and progression. While some compounds that prevent breast cancer can actually be harnessed for use by cancer cells in ways that promote tumor growth or metastasis once a tumor has become established, vitamin D appears to act synergistically to increase cancer cell death during chemotherapy and adjuvant hormonal treatment, as well as radiation treatment for breast cancer.

Radiosensitization of breast cancer cells by Vitamin D3 and Vitamin D analogs American Association for Cancer Research (AACR) Meeting, April 2010

The present study was designed to examine how vitamin D can enhance sensitivity to radiation treatment in breast cancer cells. Previous studies conducted by the authors demonstrated that the active form of vitamin D, 1,25-di hydroxy vitamin D3 (D3), or its analogs such as EB 1089, can confer enhanced sensitivity to ionizing radiation. (The vitamin D3 sold to consumers in supplement form is cholecalciferol, which is metabolized in the human body to calcitriol, otherwise known as 1,25-di hydroxy vitamin D3.)

The present study was designed to extend the previous findings to ZR-75-1 breast cancer cells (a p53 wild type ER positive cell line) using D3 combined with ionizing radiation. The effects of 100nM D3 alone, fractionated ionizing radiation (5 x 2 Gy) delivered over a period of 3 days, and 100nM D3 72 hours prior to ionizing radiation were evaluated. Radiation alone was found to reduce total cell number by approximately 30%. Pretreatment with D3 enhanced radiation sensitivity, so that the combination reduced total cell number by approximately 75%. There was no evidence of apoptosis in cells treated either with ionizing radiation alone or pretreated with D3 (as evidenced by an absence of nuclear fragmentation or chromatin condensation or cleavage of caspase-3).

Cell death was followed by a prolonged period of growth arrest under either ionizing radiation treatment alone or ionizing radiation preceded by D3. Positive ?-galactosidase staining, cell flattening and enlargement demonstrated that surviving cells after undergoing either regimen were in a state of senescence. Autophagy did not appear to be responsible for radiation sensitization in this experiment. Surprisingly, the formation of binucleated cells with micronuclei (morphology indicative of mitotic catastrophe) was evident primarily in cells pretreated with D3 prior to ionizing radiation but not in cells treated with ionizing radiation alone.

The authors conclude that pretreatment with vitamin D3 has the capacity to radiosensitize ZR-75-1 breast cancer cells by increasing the rate and extent of cell killing. Residual surviving cells after both radiation treatment alone and vitamin D pre-treatment appear to be in a state of prolonged growth arrest or senescence. While the initial mode of cell death has yet to be determined, it appears that mitotic catastrophe may play a role in vitamin D3’s radiosensitization of ZR-75-1 breast cancer cells. Taken together with the authors' previous work, the results support the theory that D3 or its analogs enhance radiation sensitivity in breast cancer cells through the promotion of multiple cell death pathways.

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See also VitaminDWiki

• Vitamin D reduces lung damage due to radiotherapy – Oct 2011
• All items in category Breast Cancer and Vitamin D 259 items
• Overview Breast Cancer and Vitamin D