This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ravid, A. Articles by Koren, R. Search for Related Content PubMed PubMed Citation Articles by Ravid, A. Articles by Koren, R.

1,25-Dihydroxyvitamin D₃ Enhances the Susceptibility of Breast Cancer Cells to Doxorubicin-induced Oxidative Damage¹

The Basil and Gerald Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, 49100 [A. R., C. R., G. K-I., U. A. L., R. K.]; Department of Physiology and Pharmacology, Sackler Faculty of Medicine [U. A. L., D. R., A. M., R. K.]; and Department of Biochemistry [A. H.], Tel-Aviv University, Tel-Aviv, 69978 Israel

1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃), the hormonal form of vitamin D, has anticancer activity in vivo and in vitro. Doxorubicin exerts its cytotoxic effect on tumor cells mainly by two mechanisms: (a) generation of reactive oxygen species (ROS); and (b) inhibition of topoisomerase II. We studied the combined cytotoxic action of 1,25(OH)₂D₃ and doxorubicin on MCF-7 breast cancer cells. Pretreatement with 1,25(OH)₂D₃ resulted in enhanced cytotoxicity of doxorubicin. The average enhancing effect after a 72-h pretreatment with 1,25(OH)₂D₃ (10 nM) followed by a 24-h treatment with 1 µg/ml doxorubicin was 74 ± 9% (mean ± SE). Under these experimental conditions, 1,25(OH)₂D₃ on its own did not affect cell number or viability. 1,25(OH)₂D₃ also enhanced the cytotoxic activity of another ROS generating quinone, menadione, but did not affect cytotoxicity induced by the topoisomerase inhibitor etoposide. The antioxidant N-acetylcysteine slightly reduced the cytotoxic activity of doxorubicin but had a marked protective effect against the combined action of 1,25(OH)₂D₃ and doxorubicin. These results indicate that ROS are involved in the interaction between 1,25(OH)₂D₃ and doxorubicin. 1,25(OH)₂D₃ also increased doxorubicin cytotoxicity in primary cultures of rat cardiomyocytes. Treatment of MCF-7 cells with 1,25(OH)₂D₃ alone markedly reduced the activity, protein, and mRNA levels of the cytoplasmic antioxidant enzyme Cu/Zn superoxide dismutase, which indicated that the hormone inhibits its biosynthesis. This reduction in the antioxidant capacity of the cells could account for the synergistic interaction between 1,25(OH)₂D₃ and doxorubicin and may also suggest increased efficacy of 1,25(OH)₂D₃ or its analogues in combination with other ROS-generating anticancer therapeutic modalities.

This article has been cited by other articles:

				V. Sharma, C. Joseph, S. Ghosh, A. Agarwal, M. K. Mishra, and E. Sen Kaempferol induces apoptosis in glioblastoma cells through oxidative stress Mol. Cancer Ther., September 1, 2007; 6(9): 2544 - 2553. [Abstract] [Full Text] [PDF]

				G. DeMasters, X. Di, I. Newsham, R. Shiu, and D. A. Gewirtz Potentiation of radiation sensitivity in breast tumor cells by the vitamin D3 analogue, EB 1089, through promotion of autophagy and interference with proliferative recovery. Mol. Cancer Ther., November 1, 2006; 5(11): 2786 - 2797. [Abstract] [Full Text] [PDF]

				M. F. McCarty and K. I. Block Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy. Integr Cancer Ther, September 1, 2006; 5(3): 252 - 268. [Abstract] [PDF]

				W. Qian, M. Nishikawa, A. Md. Haque, M. Hirose, M. Mashimo, E. Sato, and M. Inoue Mitochondrial density determines the cellular sensitivity to cisplatin-induced cell death Am J Physiol Cell Physiol, December 1, 2005; 289(6): C1466 - C1475. [Abstract] [Full Text] [PDF]

				A. V. Trevino, B. A. Woynarowska, T. S. Herman, W. Priebe, and J. M. Woynarowski Enhanced topoisomerase II targeting by annamycin and related 4-demethoxy anthracycline analogues Mol. Cancer Ther., November 1, 2004; 3(11): 1403 - 1410. [Abstract] [Full Text] [PDF]

				G. G. Schwartz, D. Eads, A. Rao, S. D. Cramer, M. C. Willingham, T. C. Chen, D. P. Jamieson, L. Wang, K. L. Burnstein, M. F. Holick, et al. Pancreatic cancer cells express 25-hydroxyvitamin D-1{alpha}-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3 Carcinogenesis, June 1, 2004; 25(6): 1015 - 1026. [Abstract] [Full Text] [PDF]

				G. Minotti, R. Ronchi, E. Salvatorelli, P. Menna, and G. Cairo Doxorubicin Irreversibly Inactivates Iron Regulatory Proteins 1 and 2 in Cardiomyocytes: Evidence for Distinct Metabolic Pathways and Implications for Iron-mediated Cardiotoxicity of Antitumor Therapy Cancer Res., December 1, 2001; 61(23): 8422 - 8428. [Abstract] [Full Text] [PDF]

				C. B. Ambrosone, C. Sweeney, B. F. Coles, P. A. Thompson, G. Y. McClure, S. Korourian, M. Y. Fares, A. Stone, F. F. Kadlubar, and L. F. Hutchins Polymorphisms in Glutathione S-Transferases (GSTM1 and GSTT1) and Survival after Treatment for Breast Cancer Cancer Res., October 1, 2001; 61(19): 7130 - 7135. [Abstract] [Full Text] [PDF]

				R. Koren, I. Hadari-Naor, E. Zuck, C. Rotem, U. A. Liberman, and A. Ravid Vitamin D Is a Prooxidant in Breast Cancer Cells Cancer Res., February 1, 2001; 61(4): 1439 - 1444. [Abstract] [Full Text]