MART-10, a New Generation of Vitamin D Analog, Is More Potent than 1α,25-Dihydroxyvitamin D₃in Inhibiting Cell Proliferation and Inducing Apoptosis in ER+ MCF-7 Breast Cancer Cells

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. 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] 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 1α,25(OH)2D3 analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), on ER+MCF-7 cells. We demonstrate that MART-10 is 500- to 1000-fold more potent than 1α,25(OH)2D3 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 1α,25(OH)2D3, possibly mediated by a greater induction of p21 and p27 expression. Moreover, MART-10 is more active than 1α,25(OH)2D3 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.

Evaluation of the potential therapeutic role of a new generation of vitamin D analog, MART-10, in human pancreatic cancer cells in vitro and in vivo

“…The results are consistent with previous reports showing that p21 and p27 were the genes targeted by 1α,25(OH) 2 D 3 and, therefore, lead to the arrest of cell growth. 14,19,52,53 Our finding is also in line with previous studies showing that 1α,25(OH) 2 D 3 and its analog could repress pancreatic cancer cell growth via cell cycle arrest at G 0 /G 1 and upregulation of p21 and p27, followed by the downregulation of cyclins and CDK. 24,28 Although other CKIs, such as p15, p18 and p19, have been implicated in G 1 /S transition, 54,55 none of them was found to be involved in the MART-10-or 1α,25(OH) 2 D 3 -mediated cell cycle arrest in BxPC-3 cells (Fig.…”

“…4C), and MART-10 is clearly much more potent than 1α,25(OH) 2 D 3 . Although 1α,25(OH) 2 D 3 has been shown to induce apoptosis in other cancer cells, 12,19 no apoptotic induction was detected in BxPC-3 cells in the current study (Fig. 3).…”

“…The procedures for protein extraction, blocking and immunodetection were described previously. 14,19 The primary antibodies used in this study were mouse monoclonal antibodies against VDR (D-6, Santa Cruz Biotechnology), P15 (Cell Signaling, #4822), P18 (Cell Signaling, #2896), P19 (BDPharMingen, 610530), p21 (Cell Signaling, #2947), p27 previously reported that 2α-(ω-hydroxypropyl)alkylated vitamin D 3 31 This property may allow MART-10 to be taken up from the circulation by pancreatic cancer cells to exert its genomic effects more easily than 1α,25(OH) 2 D 3 . Third, a cell-free reconstituted assay system has demonstrated that comparing to 1α,25(OH) 2 D 3 , MART-10 is more resistant to the CYP24A1-dependent 24-hydroxylation, the first step to degrade and terminate the actions of MART-10 and 1α,25(OH) 2 D 3 .…”

MART-10, the vitamin D analog, is a potent drug to inhibit anaplastic thyroid cancer cell metastatic potential

“…The anti-cancer characteristics of 1α,25(OH)2D3 have been widely demonstrated in recent years in a variety of cancers [7,9,18,27]. Regarding thyroid cancer, 1α,25(OH)2D3 has been shown to induce growth arrest by increasing the expression of cell cycle inhibitor p27, to restore thyroglobulin (Tg) expression indicating redifferentiation and to increase cell adhesion by increasing fibronectin expression [28][29][30].…”

“…The subsequently synthesized 19-nor-1α,25(OH)2D3 was shown to have comparable pro-differentiation effect with 1α,25(OH)2D3 and was less hypercalcemia-inducing in vivo [15]. Along this line, MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3) [16] was then synthesized and has been demonstrated by our group to be much more potent than 1α,25(OH)2D3 regarding inhibition of a variety of cancer cell growth in vitro and in vivo without obvious hypercalcemia induction [12,[17][18][19][20][21]. MART-10 has been further shown to repress cancer metastatic ability [22,23].…”