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Research Articles: Therapeutics, Targets, and Development

Potentiation of radiation sensitivity in breast tumor cells by the vitamin D₃ analogue, EB 1089, through promotion of autophagy and interference with proliferative recovery

¹ Departments of Pharmacology and Toxicology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; ² Brain Tumor Center, Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; and ³ Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

Requests for reprints: David A. Gewirtz, Massey Cancer Center, Virginia Commonwealth University, P.O. Box 980035, Richmond, VA 23298. Phone: 804-828-9523; Fax: 804-827-1134. E-mail: gewirtz{at}hsc.vcu.edu

Abstract

1,25-Dihydroxyvitamin D₃ and vitamin D₃ analogues, such as EB 1089, potentiate the response to ionizing radiation in breast tumor cells. The current studies address the basis for this interaction by evaluating DNA damage and repair, the effect of interference with reactive oxygen generation, the involvement of p53 and caspase-3, signaling through c-myc, as well as the induction of senescence and multiple modes of cell death. EB 1089 failed to increase the extent of radiation-induced DNA damage or to attenuate the rate of DNA repair. The reactive oxygen scavengers N-acetyl-L-cysteine and reduced glutathione failed to protect the cells from the promotion of cell death by EB 1089 and radiation. Whereas MCF-7 cells expressing caspase-3 showed significant apoptosis with radiation alone as well as with EB 1089 followed by radiation, EB 1089 maintained its ability to confer susceptibility to radiation-induced cell killing, in large part by interference with proliferative recovery. In contrast, in breast tumor cells lacking p53, where radiation promoted extensive apoptosis and the cells failed to recover after radiation treatment, EB 1089 failed to influence the effect of radiation. EB 1089 treatment interfered with radiation-induced suppression of c-myc; however, induction of c-myc did not prevent senescence by radiation alone or radiation-induced cell death promoted by EB 1089. EB 1089 did not increase the extent of micronucleation, indicative of mitotic catastrophe, induced by radiation alone. However, EB 1089 did promote extensive autophagic cell death in the irradiated cells. Taken together, these studies suggest that the effect of EB 1089 treatment on the radiation response is related in part to enhanced promotion of autophagic cell death and in part to interference with the proliferative recovery that occurs with radiation alone in p53 wild-type breast tumor cells. [Mol Cancer Ther 2006;5(11):2786–97]

Grant support: American Institute for Cancer Research grant 02-A068-REN, Department of Defense Predoctoral Fellowship grant DAMD 17-03-1-0414 (G. DeMasters), and NIH grant P30 CA16059 (flow cytometry).

⁴ In preparation.

Received 5/26/06; revised 7/27/06; accepted 9/11/06.

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