The vitamin D analog, MART-10, represses metastasis potential via downregulation of epithelial–mesenchymal transition in pancreatic cancer cells

• Recent evidence has indicated that the active form of vitamin D, calcitriol, has anticancer properties in addition to its well-known role as a modulator of bone and calcium metabolism. However, calcitriol can cause hypercalcemic side effect at a dose sufficient to inhibit cancer cell growth in clinical trials. Thus, more potent analogs which are either less calcemic or noncalcemic are highly desirable.
• This article describes the antimetastatic activities of MART-10 in the pancreatic cancer cells. MART-10 is a noncalcemic 19-nor, C-2 modified calcitriol analog synthesized by Dr. Kittaka of Teikyo University. The design of this compound was based on the x-ray crystallographic structure of ligand-bound vitamin D receptor complex, that shows enhanced ligand–receptor binding. Previously, we have shown that MART-10 is a potent drug to inhibit pancreatic cancer growth in vitro and in vivo without inducing side effects. In this study, we investigated the effects of MART-10 on pancreatic cancer cell invasion and migration and found MART-10 did have potent effect to inhibit pancreatic cancer metastatic potential, which warranted further clinical studies.

Pancreatic cancer (PDA) is a devastating disease and there is no effective treatment available at present. To develop new regiments against PDA is urgently needed. Previously we have shown that vitamin D analog, MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3), exerted potent antiproliferative effect on PDA in vitro and in vivo without causing hypercalcemia. Since metastasis is the major cause of PDA-related death, we therefore investigate the anti-metastasis effect of MART-10 on PDA. Our results showed that both 1α,25(OH)2D3 and MART-10 repressed migration and invasion of BxPC-3 and PANC cells with MART-10 much more potent than 1α,25(OH)2D3. 1α,25(OH)2D3 and MART-10 inhibited epithelial–mesenchymal transition (EMT) in pancreatic cancer cells through downregulation of Snail, Slug, and Vimentin expression in BxPC-3 and PANC cells. MART-10 further blocked cadherin switch (from E-cadherin to N-cadherin) in BxPC-3 cells. The F-actin synthesis in the cytoplasm of BxPC-3 cells was also repressed by 1α,25(OH)2D3 and MART-10 as determined by immunofluorescence stain. Both 1α,25(OH)2D3 and MART-10 decreased MMP-2 and -9 secretion in BxPC-3 cells as determined by western blot and zymography. Collectively, MART-10 should be deemed as a promising regimen against PDA.