Growth inhibition and differentiation in human prostate carcinoma cells induced by the vitamin D analog 1alpha,24-dihydroxyvitamin D2.
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abstract
Vitamin D has been suggested as a chemopreventive and therapeutic modality for prostate cancer. However, hypercalcemic toxicity has limited the use of 1alpha,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) in clinical trials, prompting the search for analogs of vitamin D with less toxicity while retaining efficacy as a modality for cancer intervention. In this study, the less hypercalcemic vitamin D analog 1alpha,24-dihydroxyvitamin D(2) (1,24-(OH)(2)D(2)) was examined for its effects on cellular growth inhibition and differentiation induction in the LNCaP human prostate carcinoma cell line.LNCaP cell growth was determined by quantifying DNA levels. Protein levels were determined using the ELISA method and immunoblotting. Levels of mRNA were determined using real-time quantitative reverse transcriptase PCR.LNCaP growth was decreased 50% by exposure to 0.01 nM 1,24-(OH)(2)D(2) after 96 hr in the presence of a growth stimulatory 0.1 nM dose of the androgen R1881. Prostate specific antigen (PSA) levels were increased 3.5-fold with 10 nM 1,24-(OH)(2)D(2) treatment compared to a 1.9-fold increase in PSA levels found with 10 nM 1,25-(OH)(2)D(3) under low androgen conditions. Neither 1,24-(OH)(2)D(2) nor 1,25-(OH)(2)D(3) affected the expression of cytokeratin 18 protein levels. Treatment with 10 nM 1,24-(OH)(2)D(2) alone produced a 1.3-fold increase in AR mRNA and a 2.2-fold increase in AR protein levels after 96 hr. Surprisingly, the addition of 1.0 nM R1881 alone or in combination with 10 nM 1,24-(OH)(2)D(2) produced an approximately 60% decrease in AR mRNA, whereas AR protein levels were increased 1.6-fold.Overall, 1,24-(OH)(2)D(2) was found to be at least as effective as 1,25-(OH)(2)D(3) at inhibiting growth and inducing differentiation markers in LNCaP prostate carcinoma cells and may thus prove useful in prostate cancer treatment.Copyright 2003 Wiley-Liss, Inc.
