Abstract

Studies in our laboratory demonstrate that vitamin D or 1,25- dihy6droxycholecalciferol (calcitriol) has significant anti proliferative activity in vivo and in vitro. Calcitriol induces G0/G1 arrest, modulates expression of p27/p21, induces PARP cleavage, increases the bax/bcl-2 ratio and enhances the anti-tumor activity of cisplatin, carboplatin and paclitaxel. Dexamethasone (dex) potentiates calcitriol-mediated anti- tumor activity and vitamin D receptor (VDR) ligand binding in vitro and in vivo whereas equivalent doses of methylpredinsolone (mp) do not. Both dex and mp enhance VDR protein expression; however, calcitriol plus dex results in an increase in retinoid X receptor (RXR) alpha levels and calcitriol/mp decreases RXRalpha. Calcitriol/dex suppresses activity mitogen-activated protein kinase ( MAPK) activity while calcitriol/mp have no effect. In a phase II clinical trial of hormone refractory prostate cancer with oral calcitriol and dex, we observed a 50% reduction in prostate specific antigen (PSA) in 31% of patients with no hypercalcemia and a modulation of VDR from peripheral blood monocytes. We propose to determine the mechanisms of calcitriol and dex/mp interaction by the following specific aims: 1) To determine the mechanisms involved in glucocorticoid effects on tumor cells by examining: a) the role of steroid binding to the glucocorticoid receptor (GR); b) the differential role of RXR; and c) whether glucocorticoid effects require calcitriol binding to the VDR, modulate binding to the VDRE, and/or tumor model systems by determining: a) the effect on receptor (VDR/GR) and non-receptor (MAPK) mediated activities, and b) the role of RXR; and 3) To evaluate oral calcitriol and dex in hormone refractory prostate cancer through conduct of a phase I trial to determine: a) the maximum tolerated dose (MTD), toxicities and calcitriol pharmacokinetics, b) the clinical and PSA response, and 4) modulation of peripheral blood monocyte VDR, RXR and MAPK activity by calcitriol and calcitriol/dex.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA085142-01
Application #
6077007
Study Section
Special Emphasis Panel (ZRG1-ET-1 (04))
Program Officer
Xie, Heng
Project Start
2000-02-01
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$303,771
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Ma, Yingyu; Hu, Qiang; Luo, Wei et al. (2015) 1?,25(OH)2D3 differentially regulates miRNA expression in human bladder cancer cells. J Steroid Biochem Mol Biol 148:166-71
Luo, Wei; Hershberger, Pamela A; Trump, Donald L et al. (2013) 24-Hydroxylase in cancer: impact on vitamin D-based anticancer therapeutics. J Steroid Biochem Mol Biol 136:252-7
Ma, Yingyu; Yu, Wei-Dong; Su, Bing et al. (2013) Regulation of motility, invasion, and metastatic potential of squamous cell carcinoma by 1ýý,25-dihydroxycholecalciferol. Cancer 119:563-74
Luo, Wei; Yu, Wei-Dong; Ma, Yingyu et al. (2013) Inhibition of protein kinase CK2 reduces Cyp24a1 expression and enhances 1,25-dihydroxyvitamin D(3) antitumor activity in human prostate cancer cells. Cancer Res 73:2289-97
Luo, Wei; Hu, Qiang; Wang, Dan et al. (2013) Isolation and genome-wide expression and methylation characterization of CD31+ cells from normal and malignant human prostate tissue. Oncotarget 4:1472-83
Ma, Yingyu; Yu, Wei-Dong; Hidalgo, Alejandro A et al. (2013) Inecalcitol, an analog of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system. Cell Cycle 12:743-52
Hidalgo, Alejandro A; Deeb, Kristin K; Pike, J Wesley et al. (2011) Dexamethasone enhances 1alpha,25-dihydroxyvitamin D3 effects by increasing vitamin D receptor transcription. J Biol Chem 286:36228-37
Deeb, Kristin K; Luo, Wei; Karpf, Adam R et al. (2011) Differential vitamin D 24-hydroxylase/CYP24A1 gene promoter methylation in endothelium from benign and malignant human prostate. Epigenetics 6:994-1000
Woloszynska-Read, Anna; Johnson, Candace S; Trump, Donald L (2011) Vitamin D and cancer: clinical aspects. Best Pract Res Clin Endocrinol Metab 25:605-15
Muindi, Josephia R; Yu, Wei-Dong; Ma, Yingyu et al. (2010) CYP24A1 inhibition enhances the antitumor activity of calcitriol. Endocrinology 151:4301-12

Showing the most recent 10 out of 36 publications