Efficacy and Mechanism of Action of 1α-hydroxy-24-ethyl-Cholecalciferol (1α[OH]D5) in Breast Cancer Prevention and Therapy
It is now well established that the active metabolite of vitamin D3, 1α,25(OH)2D3, regulates cell growth and differentiation in various in vitrocancer models. However, its clinical use is precluded due to its hypercalcemicactivity in vivo. Hence, several less calcemic vitamin D analogs have been synthesizedand evaluated for their chemopreventive and therapeutic efficacy inexperimental carcinogenesis models. A novel analog of vitamin D3, 1α-hydroxy-24-ethyl-cholecalciferol (1α[OH]D5), has currently been under investigationin our laboratory for its application in breast cancer prevention andtherapy. 1α(OH)D5 had been shown to inhibit development of estrogen-andprogesterone-dependent ductal lesions as well as steroid hormone-independentalveolar lesions in a mammary gland organ culture (MMOC) model. Moreover, the inhibitory effect was more significant if 1α(OH)D5 was presentduring the promotional phase of the lesion development. The growth inhibitoryeffect of 1α(OH)D5 has also been manifested in several breast cancer celllines, including BT-474 and MCF-7. Breast cancer cell lines that responded to1a(OH)D5 treatment were vitamin D receptor positive (VDR+). Vitamin D receptor-negative (VDR_) cell lines, such as MDA-MB-231 and MDA-MB-435, did not show growth inhibition upon incubation with 1α(OH)D5.
KeywordsBreast Cancer Mammary Gland Progesterone Receptor Breast Cancer Prevention Calcemic Activity
Unable to display preview. Download preview PDF.
- Demirpence E, Balaguer P, Trousse F, Nicolas JC, Pons M, Gagne D (1994) Antiestrogenic effects of all-trans-retinoic acid and 1a,25-dihydroxyvitamin D3 in breast cancer cells occur at the estrogen response element level but through different molecular mechanisms. Cancer Res 54:1458–1464PubMedGoogle Scholar
- Edwards BK, Howe HL, Ries LA, Thun MJ, Rosenberg HM, Yancik R, Wingo PA, Jemal A,Feigal EG (2002) Annual Report to the Nation on the status of cancer, 1973–1999, featuring implications of age and aging on U.S. cancer burden. Cancer 94:2766–2792Google Scholar
- Gallegos A, Gasdaska JR, Taylor CW, Paine-Murrieta GD, Goodman D, Gasdaska PY,Berggren M, Briehl MM, Powis G (1996) Transfection with human thioredoxin increases cell proliferation and a dominant-negative mutant thioredoxin reverses the transformed phenotype of human breast cancer cells. Cancer Res 56:5765–5770Google Scholar
- Kelloff GJ, Boone CW, Crowell JA, Steele VE (1996) New agents for cancer chemoprevention.J Cell Biochem 26 [Suppl]:1–28Google Scholar
- Lazzaro G, Agadir A, Qing W, Poria M, Mehta RR, Moriarty RM, Das-Gupta TK, Zhang XK,Mehta RG (2000) Induction of differentiation by 1a(OH)D5 in T-47D breast cancer cellsand its interaction with vitamin D receptors. Eur J Cancer 36:780–786Google Scholar
- Matsutani Y, Yamauchi A, Takahashi R, Ueno M, Yoshikawa K, Honda K, Nakamura H, Kato H, Kodama H, Inamoto T, Yodoi J, Yamaoka Y (2001) Inverse correlation of thioredoxin expression with estrogen receptor-and p53-dependent tumor growth in breast cancer tissues.Clin Cancer Res 7:3430–436Google Scholar
- Mehta RG, Hussain EA, Mehta RR, Das-Gupta TK (2003) Chemoprevention of mammary carcinogenesis by 1a-hydroxy vitamin D5, a synthetic analog of vitamin D. Mut Res (in press)Google Scholar
- Rachez C, Freedman LP (2000) Mechanism of gene regulation by VDR: a network of coactivator interactions. Genes 246:9–21Google Scholar
- Roder JD, Stair E (1999) An overview of cholecalciferol toxicosis. Vet Human Toxicol 4:344–348Google Scholar