Doxazosin induces apoptosis in LNCaP prostate cancer cell line through DNA binding and DNA-dependent protein kinase down-regulation.
Doxazosin is a quinazoline-based compound acting as an alpha-1-adrenergic inhibitor shown to induce apoptosis in prostate cancer cell lines via an alpha-1-adrenergic receptor-independent mechanism. To better understand the mechanism of doxazosin-induced apoptosis in prostate cancer, we performed cDNA microarray to analyze gene expression changes produced by doxazosin in the androgen-dependent human prostate cancer cell line, LNCaP. We found that 70 and 92 genes were deregulated after 8 and 24 h of doxazosin treatment, respectively. These genes are involved in several cellular processes such as cell-cycle regulation, cell adhesion and signal transduction pathways. Strikingly, we found that doxazosin induces deregulation of genes implicated in DNA replication and repair, such as GADD45A, XRCC5 and PRKDC. These facts, together with the demonstration of the ability of doxazosin to bind DNA, allowed us to propose a novel mechanism of action for doxazosin in prostate cancer cells that implies DNA-damage mediated apoptosis by down-regulation of XRCC5 and PRKDC genes.
Arencibia
José M
JM
Departamento de Bioquímica, Facultad de CC. Biosanitarias, Universidad Francisco de Vitoria, Ctra. 28223 Madrid, Spain.
Del Rio
Mónica
M
Bonnin
Ana
A
Lopes
Rita
R
Lemoine
Nicholas R
NR
López-Barahona
Mónica
M
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism*; D004278:DNA, Superhelical / Q000737:chemistry / Q000235:genetics; D051747:DNA-Activated Protein Kinase / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D017292:Doxazosin / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D009690:Nucleic Acid Conformation / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010957:Plasmids / Q000737:chemistry / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000317:Adrenergic alpha-Antagonists; D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D051747:DNA-Activated Protein Kinase; D017292:Doxazosin