19-nor-1 alpha,25-dihydroxyvitamin D2 (paricalcitol) inhibits the proliferation of human pancreatic cancer cells in vitro and in vivo.
1,25-dihydroxyvitamin D(3), (1,25(OH)(2)D(3); calcitriol), the hormonal form of vitamin D, exerts growth-inhibitory, pro-apoptotic and anti-metastatic effects on tumor cells in vitro and in vivo but its clinical use is limited by its calcemic effects. Previous studies have shown that the antiproliferative effects of the less calcemic calcitriol analog 19-nor-1,25-(OH)(2)D(2) (paricalcitol) on prostate tumor cell lines are indistinguishable from those of 1,25(OH)(2)D(3). We therefore investigated the anti-proliferative effects of paricalcitol on the growth of pancreatic tumor cell lines in vitro and in vivo. Both 1,25(OH)(2)D(3) and paricalcitol inhibited the growth of BxPC-3, Hs700T and AsPC-1 lines in a dose-dependent manner. This antiproliferative activity correlated with upregulation of the cell cycle inhibitors p21 (Waf1/CIP1) and p27(Kip1). A fourth pancreatic cell line, Hs766T was unresponsive to both paricalcitol and calcitriol. Hs766T cells also failed to upregulate p21/Waf-1/Cip1 or p27/KiP in response to treatments with these agents. Paricalcitol, given three times per week inhibited the growth of AsPC-1 pancreatic tumor cell xenografts in nude mice at a dose that did not cause hypercalcaemia. Tumor inhibition was accompanied by in vivo upregulation of p21 and p27 expression. Given the few therapeutic options for patients with pancreatic cancer, further exploration of paricalcitol, an FDA-approved medication, is warranted.
Schwartz
Gary G
GG
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. gschwart@wfubmc.edu
Eads
Dawn
D
Naczki
Christine
C
Northrup
Scott
S
Chen
Tai
T
Koumenis
Constantinos
C
D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004872:Ergocalciferols / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*
D050071:Bone Density Conservation Agents; D004872:Ergocalciferols; C084656:paricalcitol