vitamin-d-2 and Carcinoma--Squamous-Cell

New vitamin D analogs are interesting candidates for anticancer treatment, including squamous cell carcinomas (SCCs), especially in combination with cytostatics. In order to evaluate the effect of combined application of cisplatin, imatinib, or docetaxel and new vitamin D analogs [PRI-1906: (24E)-24a-homo-(1S)-1,25-dihydroxyergocalciferol, and PRI-2191: (24R)-1,24-dihydroxyvitamin D3], against the cells of two human SCCs lines (SCC-25 and FaDu), cytotoxic activity and the effect on cell cycle and apoptosis were determined. The synergistic or additive antiproliferative effect was observed for all cytostatics used after treatment of FaDu cell line with calcitriol or its analogs. Antagonism caused by combination of calcitriol and docetaxel was shown only in the lowest dose. FaDu cells treated with cytostatics and vitamin D analogs cumulated in G0/G1 stage. A statistically significant decrease (2x) in the percentage of apoptotic cells was observed only in combination of imatinib and calcitriol or PRI-1906. On the other hand, when the SCC-25 cell line incubated with cisplatin and imatinib in combination with calcitriol or PRI-2191 (100 nM) was used, the quantitative method of Chou and Talalay indicated antagonism. In the lower doses of calcitriol or PRI-2191 combined with imatinib, the synergistic effect was observed, but in the case of combination with cisplatin or docetaxel only weak additivity was detected. Moreover, a significant decrease (2x) of the percentage of SCC-25 cells undergoing apoptosis induced by docetaxel, cisplatin, and imatinib was observed. The combination of all cytostatic drugs applied with PRI-1906 in all doses caused synergism or additivity. These results might indicate that PRI-1906 is more effective than calcitriol or PRI-2191 as a potential anticancer agent, when used in combination therapy with cytostatic agents. To our knowledge, this is the first observation of interaction with calcitriol or its analogs and imatinib.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Calcitriol; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cisplatin; Dihydroxycholecalciferols; Docetaxel; Dose-Response Relationship, Drug; Drug Synergism; Ergocalciferols; G1 Phase; Head and Neck Neoplasms; Humans; Imatinib Mesylate; Piperazines; Pyrimidines; Resting Phase, Cell Cycle; Taxoids

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.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Bromodeoxyuridine; Calcitriol; Carcinoma, Squamous Cell; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; DNA, Neoplasm; Ergocalciferols; MAP Kinase Kinase Kinase 1; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C3H; Mitogen-Activated Protein Kinase 3; Oncogene Protein v-akt; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction

Topics: Administration, Topical; Alkaline Phosphatase; Animals; Benz(a)Anthracenes; Body Weight; Calcium; Carcinoma, Squamous Cell; Cell Membrane; Cell Membrane Permeability; Cheek; Cholecalciferol; Cricetinae; Ergocalciferols; Male; Models, Biological; Mouth Mucosa; Mouth Neoplasms; Neoplasms, Experimental; Protein Binding; Spectrophotometry