Vitamin D2 analog 19-nor-1,25-dihydroxyvitamin D2: antitumor activity against leukemia, myeloma, and colon cancer cells.
BACKGROUND
1,25-Dihydroxyvitamin D(3) inhibits growth of several types of human cancer cells in vitro, but its therapeutic use is hampered because it causes hypercalcemia. 19-nor-1,25-Dihydroxyvitamin D(2) (paricalcitol) is a noncalcemic vitamin D analog that is approved by the Food and Drug Administration for the treatment of secondary hyperparathyroidism. We investigated the antitumor activity and mechanism of action of paricalcitol in vitro and in vivo.


METHODS
Effects of paricalcitol on proliferation, the cell cycle, differentiation, and apoptosis were examined in cancer cell lines. Effects on tumor growth were examined with colon cancer cell xenografts in nude mice (five in the experimental group and five in the control group). The interaction of paricalcitol with the vitamin D receptor (VDR) in mononuclear spleen cells and myeloid stem cells from wild-type and VDR knockout mice was examined. All statistical tests were two-sided.


RESULTS
Paricalcitol inhibited the proliferation of myeloid leukemia cell lines HL-60, NB-4, and THP-1 cells at an effective dose that inhibited growth 50% (ED(50)) of 2.4-5.8 x 10(-9) M by inducing cell cycle arrest and differentiation. Paricalcitol inhibited the proliferation of NCI-H929 myeloma cells at an ED(50) of 2.0 x 10(-10) M by inducing cell cycle arrest and apoptosis. Paricalcitol also inhibited the proliferation of colon cancer cell lines HT-29 (ED(50) = 1.7 x 10(-8) M) and SW837 (ED(50) = 3.2 x 10(-8) M). HT-29 colon cancer xenografts in paricalcitol-treated nude mice were smaller (1044 mm(3) and 1752 mm(3), difference = 708 mm(3), 95% confidence interval = 311 to 1104 mm(3); P =.03) and weighed less (1487 mg and 4162 mg, difference = 2675 mg, 95% confidence interval = 2103 to 3248 mg; P<.001) than those in vehicle-treated mice. Paricalcitol induced committed myeloid hematopoietic stem cells from wild-type but not from VDR knockout mice to differentiate as macrophages.


CONCLUSIONS
Paricalcitol has anticancer activity against myeloid leukemia, myeloma, and colon cancer cells that may be mediated through the VDR. Because it has been approved by the Food and Drug Administration, clinical trials of this agent in certain cancers are reasonable.
Kumagai
Takashi
T
Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, 90048, USA. kumamed1_2001@yahoo.co.jp
O'Kelly
James
J
Said
Jonathan W
JW
Koeffler
H Phillip
HP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004872:Ergocalciferols / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy*; D016133:Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004872:Ergocalciferols; D018167:Receptors, Calcitriol; C084656:paricalcitol