title: AZD1152-HQPA induces growth arrest and apoptosis in androgen-dependent prostate cancer cell line (LNCaP) via producing aneugenic micronuclei and polyploidy.
abstract: Prostate cancer is the frequent non-cutaneous tumor with high mortality in men. Prostate tumors contain cells with different status of androgen receptor. Androgen receptor plays important roles in progression and treatment of prostate cancer. Aurora B kinase, with oncogenic potential, is involved in chromosome segregation and cytokinesis, and its inhibition is a promising anti-cancer therapy. In the present study, we aimed to investigate the effects of Aurora B inhibitor, AZD1152-HQPA, on survival and proliferation of androgen receptor (AR)-positive prostate cancer cells. LNCaP was used as androgen-dependent prostate cancer cell line. We explored the effects of AZD1152-HQPA on cell viability, DNA content, micronuclei formation, and expression of genes involved in apoptosis and cell cycle. Moreover, the expression of Aurora B and AR were investigated in 23 benign prostatic hyperplasia and 38 prostate cancer specimens. AZD1152-HQPA treatment induced defective cell survival, polyploidy, and cell death in LNCaP cell line. Centromeric labeling with fluorescence in situ hybridization (FISH) showed that the loss of whole chromosomes is the origin of micronuclei, indicating on aneugenic action of AZD1152-HQPA. Treatment of AZD1152-HQPA decreased expression of AR. Moreover, we found weak positive correlations between the expression of Aurora B and AR in both benign prostatic hyperplasia and prostate cancer specimens (r = 0.25, r = 0.41). This is the first time to show that AZD1152-HQPA can be a useful therapeutic strategy for the treatment of androgen-dependent prostate cancer cell line. AZD1152-HQPA induces aneugenic mechanism of micronuclei production. Taken together, this study provides new insight into the direction to overcome the therapeutic impediments against prostate cancer.
authors.affiliation: Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Zekri
authors.forename: Seyed H
authors.initials: SH
authors.lastname: Ghaffari
authors.forename: Samad
authors.initials: S
authors.lastname: Ghanizadeh-Vesali
authors.forename: Marjan
authors.initials: M
authors.lastname: Yaghmaie
authors.forename: Arash
authors.initials: A
authors.lastname: Salmaninejad
authors.forename: Kamran
authors.initials: K
authors.lastname: Alimoghaddam
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Modarressi
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Ghavamzadeh
mesh_terms: D024422:Aneugens / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D010755:Organophosphates / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage*; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D024422:Aneugens; D010755:Organophosphates; D011799:Quinazolines; D011944:Receptors, Androgen; C576921:AURKB protein, human; D064107:Aurora Kinase B