MART-10, a New Generation of Vitamin D Analog, Is More Potent than 1α, 25-Dihydroxyvitamin D3 in Inhibiting Cell Proliferation and Inducing Apoptosis in ER+ MCF-7 Breast Cancer Cells. (11th December 2012) - Chiang, Kun-Chun
Abstract : Hormone antagonist therapy for estrogen receptor positive (ER+) breast cancer patients post radical surgery and radiation therapy has a poor prognosis and also causes bone loss. 1 α, 25-dihydroxyvitamin D3 [1 α, 25(OH)2 D3 ] is a potent antitumor agent in pre-clinical studies, but caused hypercalcemia when its effective antitumor doses were used. Therefore, we investigated the effects of a less-calcemic 1 α, 25(OH)2 D3 analog, 19-nor-2 α -(3-hydroxypropyl)-1 α, 25-dihydroxyvitamin D3 (MART-10), on ER+MCF-7 cells. We demonstrate that MART-10 is 500- to 1000-fold more potent than 1 α, 25(OH)2 D3 in inhibiting cell growth in a dose- and time-dependent manner. MART-10 is also much more potent in arresting MCF-7cell cycle progression at G0 /G1 phase as compared to 1 α, 25(OH)2 D3, possibly mediated by a greater induction of p21 and p27 expression. Moreover, MART-10 is more active than 1 α, 25(OH)2 D3 in causing cell apoptosis, likely through a higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol. Based on our in vitro findings, MART-10 could be a promising vitamin D analog for the potential treatment of breast cancer, for example, ER+ patients, to decrease the tumor relapse rate and the side effect on bone caused by antihormone regimens. Thus, further in vivo animal study is warranted.