Checkpoint kinase inhibitor synergizes with DNA-damaging agents in G 1 checkpoint-defective neuroblastoma Journal Article


Authors: Xu, H.; Cheung, I. Y.; Wei, X. X.; Tran, H.; Gao, X.; Cheung, N. K. V.
Article Title: Checkpoint kinase inhibitor synergizes with DNA-damaging agents in G 1 checkpoint-defective neuroblastoma
Abstract: Checkpoint kinase inhibitors can enhance the cancer killing action of DNA-damaging chemotherapeutic agents by disrupting the S/G2 cell cycle checkpoints. The in vitro and in vivo effects of the Chk1/2 inhibitor AZD7762 when combined with these agents were examined using neuroblastoma cell lines with known p53/MDM2/p14ARF genomic status. Four of four p53 mutant lines and three of five MDM2/p14ARF abnormal lines were defective in G1 checkpoint, correlating with failure to induce endogenous p21 after treatment with DNA-damaging agents. In cytotoxicity assays, these G1 checkpoint-defective lines were more resistant to DNA-damaging agents when compared to G1 checkpoint intact lines, yet becoming more sensitive when AZD7762 was added. Moreover, AZD7762 abrogated DNA damage-induced S/G2 checkpoint arrest both in vitro and in vivo. In xenograft models, a significant delay in tumor growth accompanied by histological evidence of increased apoptosis was observed, when AZD7762 was added to the DNA-damaging drug gemcitabine. These results suggest a therapeutic potential of combination therapy using checkpoint kinase inhibitor and chemotherapy to reverse or prevent drug resistance in treating neuroblastomas with defective G1 checkpoints. Copyright © 2010 UICC.
Keywords: controlled study; human tissue; unclassified drug; human cell; histopathology; cisplatin; doxorubicin; cancer combination chemotherapy; cancer growth; drug potentiation; nonhuman; gemcitabine; topotecan; antineoplastic agent; mutant protein; mouse; animal tissue; dna damage; cell cycle s phase; apoptosis; multiple cycle treatment; etoposide; animal experiment; animal model; 7 ethyl 10 hydroxycamptothecin; melphalan; in vivo study; in vitro study; tumor xenograft; drug effect; chemosensitivity; cell assay; protein p53; cancer resistance; vincristine sulfate; drug mechanism; neuroblastoma; cell cycle arrest; genomics; cell cycle checkpoint; cell cycle g2 phase; drug cytotoxicity; cyclin dependent kinase inhibitor 2a; drug treatment failure; cell cycle g1 phase; phosphotransferase inhibitor; protein mdm2; nocodazole; chk1; protein defect; azd 7762; azd7762; synergism; [3 (carbamoylamino) 5 (3 fluorophenyl) n (3 piperidyl)thiophene 2 carboxamide]
Journal Title: International Journal of Cancer
Volume: 129
Issue: 8
ISSN: 0020-7136
Publisher: John Wiley & Sons  
Date Published: 2011-10-15
Start Page: 1953
End Page: 1962
Language: English
DOI: 10.1002/ijc.25842
PROVIDER: scopus
PUBMED: 21154747
DOI/URL:
Notes: --- - "Export Date: 3 October 2011" - "CODEN: IJCNA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Nai-Kong Cheung
    447 Cheung
  2. Irene Y Cheung
    75 Cheung
  3. Hong Xu
    23 Xu
  4. Xiao Xiao Wei
    2 Wei
  5. Xiaoni Gao
    2 Gao
  6. Hoa   Tran
    4 Tran