Antitumor effects of two less-calcemic vitamin D analogs (Paricalcitol and QW-1624F2-2) in squamous cell carcinoma cells.
The active metabolite of vitamin D(3) (1alpha,25-dihydroxyvitamin D(3), calcitriol) has potent antitumor activities in vitro and in vivo in multiple cancers. Concerns about induction of hypercalcemia by calcitriol and the desire for more potent agents have prompted development of less-calcemic vitamin D analogs. These studies demonstrate that two vitamin D analogs, 19-nor-1alpha,25-dihydroxyvitamin D(2) (paricalcitol) and 1alpha-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D(3) (QW-1624F(2)-2, QW), have anticancer effects in the calcitriol-responsive squamous cell carcinoma (SCC) cell line. Paricalcitol (GI50 = 0.7 nM) and QW (GI50 = 0.001 nM) inhibited SCC cell growth; however, QW was more potent. Paricalcitol (10 nM) and QW (10 nM) induced G0/G1 cell cycle arrest and inhibited DNA synthesis by approximately 95%. The vitamin D analogs modulated cell cycle regulators, including decreasing mRNA and protein levels of p21(Waf1/Cip1) (p21) and cyclin-dependent kinase 2 (cdk2), and increasing p27(Kip1) (p27) protein expression. Vitamin D analogs induced apoptosis, caspase-3 cleavage and increased expression of pro-apoptotic MEKK-1. Phosphorylation of Akt, MEK and ERK1/2 that promote cell growth and survival were inhibited by vitamin D analogs. The anticancer effects of paricalcitol and QW are comparable to the effect of calcitriol. These less-calcemic vitamin D analogs are as effective as calcitriol in vitro and are promising for prevention and treatment of cancer and other diseases.
Alagbala
Adebusola A
AA
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, N.Y., USA.
Johnson
Candace S
CS
Trump
Donald L
DL
Posner
Gary H
GH
Foster
Barbara A
BA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects; D004872:Ergocalciferols / Q000494:pharmacology*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004273:DNA, Neoplasm; D004872:Ergocalciferols; C113641:QW 1624F2-1; C084656:paricalcitol; D051058:Oncogene Protein v-akt; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D048052:Mitogen-Activated Protein Kinase 3; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D002117:Calcitriol; D001973:Bromodeoxyuridine