The checkpoint kinase inhibitor AZD7762 potentiates chemotherapy-induced apoptosis of p53-mutated multiple myeloma cells Journal Article

  


Authors: Landau, H. J.; McNeely, S. C.; Nair, J. S.; Comenzo, R. L.; Asai, T.; Friedman, H.; Jhanwar, S. C.; Nimer, S. D.; Schwartz, G. K.
Article Title: The checkpoint kinase inhibitor AZD7762 potentiates chemotherapy-induced apoptosis of p53-mutated multiple myeloma cells
Abstract: DNA cross-linking agents are frequently used in the treatment of multiple myeloma-generating lesions, which activate checkpoint kinase 1 (Chk1), a critical transducer of theDNA damage response. Chk1 activation promotes cell survival by regulating cell-cycle arrest andDNA repair following genotoxic stress. The ability of AZD7762, an ATP-competitive Chk1/2 inhibitor to increase the efficacy of the DNA-damaging agents bendamustine, melphalan, and doxorubicin was examined using four human myeloma cell lines, KMS-12- BM, KMS-12-PE, RPMI-8226, and U266B1. The in vitro activity of AZD7762 as monotherapy and combined with alkylating agents and the "novel" drug bortezomib was evaluated by studying its effects on cytotoxicity, signaling, and apoptotic pathways. The Chk1/2 inhibitor AZD7762 potentiated the antiproliferative effects of bendamustine, melphalan, and doxorubicin but not bortezomib in multiple myeloma cell lines that were p53- deficient. Increased γH2AXstaining in cells treated with bendamustine or melphalan plus AZD7762 indicates a greater degree of DNA damage with combined therapy. Abrogation of the G2-M checkpoint by AZD7762 resulted in mitotic catastrophe with ensuing apoptosis evidenced by PARP and caspase-3 cleavage. In summary, the cytotoxic effects of bendamustine, melphalan and doxorubicin on p53-deficient multiple myeloma cell lines were enhanced by the coadministration of AZD7762. These data provide a rationale for testing these combinations in patients with relapsed and/or refractory multiple myeloma. ©2012 AACR.
Keywords: signal transduction; controlled study; human cell; mutation; doxorubicin; cancer combination chemotherapy; drug efficacy; drug potentiation; monotherapy; antineoplastic agents; dna damage; cell cycle; apoptosis; bortezomib; multiple myeloma; protein kinases; alkylating agent; bendamustine; melphalan; caspase 3; cytotoxicity; drug structure; enzyme activation; in vitro study; cell line, tumor; protein p53; drug synergism; protein kinase inhibitors; dna; tumor suppressor protein p53; checkpoint kinase 1; protein cleavage; urea; antiproliferative activity; thiophenes; myeloma cell; dna content; 5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide; micronuclei, chromosome-defective
Journal Title: Molecular Cancer Therapeutics
Volume: 11
Issue: 8
ISSN: 1535-7163
Publisher: American Association for Cancer Research  
Date Published: 2012-08-01
Start Page: 1781
End Page: 1788
Language: English
DOI: 10.1158/1535-7163.mct-11-0949
PROVIDER: scopus
PUBMED: 22653969
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84864877535&partnerID=40&md5=ff12107981fc052aac28cc0ee11b9409
Notes: --- - "Export Date: 4 September 2012" - "CODEN: MCTOC" - "Source: Scopus"
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MSK Authors
  1. Gary Schwartz
    385 Schwartz
  2. Stephen D Nimer
    347 Nimer
  3. Heather Jolie Landau
    419 Landau
  4. Takashi Asai
    12 Asai
  5. Samuel C Mc Neely
    3 Mc Neely
  6. Jayasree Nair
    17 Nair
  7. Suresh C Jhanwar
    293 Jhanwar
  8. Hillel Friedman
    1 Friedman
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