title: 17alpha-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response.
abstract: Inhibitors of the enzyme 17alpha-hydroxylase/17,20 lyase are a new class of anti-prostate cancer agents currently undergoing preclinical and clinical development. We have previously reported the superior anticancer activity of our novel 17alpha-hydroxylase/17,20 lyase inhibitor, VN/124-1, against androgen-dependent cancer models. Here, we examined the effect of VN/124-1 on the growth of the androgen-independent cell lines PC-3 and DU-145 and found that the compound inhibits their growth in a dose-dependent manner in vitro (GI50, 7.82 micromol/L and 7.55 micromol/L, respectively). We explored the mechanism of action of VN/124-1 in PC-3 cells through microarray analysis and found that VN/124-1 up-regulated genes involved in stress response and protein metabolism, as well as down-regulated genes involved in cell cycle progression. Follow-up real-time PCR and Western blot analyses revealed that VN/124-1 induces the endoplasmic reticulum stress response resulting in down-regulation of cyclin D1 protein expression and cyclin E2 mRNA. Cell cycle analysis confirmed G1-G0 phase arrest. Measurements of intracellular calcium levels ([Ca2+]i) showed that 20 micromol/L VN/124-1 caused a release of Ca2+ from endoplasmic reticulum stores resulting in a sustained increase in [Ca2+]i. Finally, cotreatment of PC-3 cells with 5, 10, and 20 micromol/L VN/124-1 with 10 nmol/L thapsigargin revealed a synergistic relationship between the compounds in inhibiting PC-3 cell growth. Taken together, these findings show VN/124-1 is endowed with multiple anticancer properties that may contribute to its utility as a prostate cancer therapeutic.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Bruno
authors.forename: Tony D
authors.initials: TD
authors.lastname: Gover
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Burger
authors.forename: Angela M
authors.initials: AM
authors.lastname: Brodie
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
mesh_terms: D000728:Androgens / Q000378:metabolism; D000730:Androstadienes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics / Q000473:pathology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D019284:Thapsigargin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000728:Androgens; D000730:Androstadienes; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; D019938:Cyclin D1; D019284:Thapsigargin; D013254:Steroid 17-alpha-Hydroxylase; D002118:Calcium; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene
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