Inhibitor of Aurora Kinase B Induces Differentially Cell Death and Polyploidy via DNA Damage Response Pathways in Neurological Malignancy: Shedding New Light on the Challenge of Resistance to AZD1152-HQPA.
Aurora kinase B (AURKB), a crucial regulator of malignant mitosis, is involved in chromosome segregation and cytokinesis. AZD1152-HQPA is a selective inhibitor for AURKB activity and currently bears clinical assessment for several malignancies. However, the effect of this drug still needs to be elucidated in neurological malignancies. In this study, we investigated the restrictive potentials of AZD1152-HQPA in U87MG and SK-N-MC. AZD1152-HQPA treatment resulted in growth arrest, modification of cell cycle, and inhibition of colony formation in both cell lines. Furthermore, lower concentrations of AZD1152-HQPA profoundly induced apoptosis in U87GM (p53/p73 wild type) cells in parallel with an upregulation of p53 and its target genes BAX, BAD, APAF1, and PUMA. But remarkably, SK-N-MC (p53/p73 double null) responded to AZD1152-HQPA at much higher concentrations with an upregulation of genes involved in cell cycle progression, induction of excessive endoreduplication, and polyploidy rather than apoptosis. Although SK-N-MC was resistant to AZD1152-HQPA, we did not find a mutation in the coding sequence of Aurora B gene or overexpressions of ABCG2 and ABCB1 as reported previously to be resistance mechanisms. However, our results suggest that p53/p73 status could be an important mechanism for the type of response and resistance of the tumor cells to AZD1152-HQPA. Collectively, inhibition of Aurora kinase B differentially induced cell death and polyploidy via DNA damage response pathways, depending on the status of p53/p73. We suggest p53/p73 could be a key regulator of sensitivity to AZD1152-HQPA and their status should be explored in clinical response to this ongoing drug in clinical trials.
Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.|Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Ali
A
Zekri
Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. shghaffari200@yahoo.com.
Seyed H
SH
Ghaffari
Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Marjan
M
Yaghmaie
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Mehrdad Asghari
MA
Estiar
Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Kamran
K
Alimoghaddam
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Mohammad Hossein
MH
Modarressi
Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Ardeshir
A
Ghavamzadeh
D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048631:Micronucleus, Germline / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010755:Organophosphates / Q000494:pharmacology* / Q000627:therapeutic use; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D014410:Tumor Stem Cell Assay
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; D004273:DNA, Neoplasm; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D064107:Aurora Kinase B; D053148:Caspase 3
AZD1152-HQPA; DNA damage response pathway; Mitotic catastrophe; Neurological malignancies; P53/p73 status