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

Heather J. Landau, Samuel C. McNeely, Jayasree S. Nair, Raymond L. Comenzo, Takashi Asai, Hillel Friedman, Suresh C. Jhanwar, Stephen D Nimer, Gary K. Schwartz

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1781-1788
Number of pages8
JournalMolecular Cancer Therapeutics
Volume11
Issue number8
DOIs
StatePublished - Aug 1 2012
Externally publishedYes

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Multiple Myeloma
Melphalan
Phosphotransferases
Apoptosis
Drug Therapy
Checkpoint Kinase 2
Doxorubicin
Cell Line
DNA Damage
Alkylating Agents
DNA
Cell Cycle Checkpoints
Transducers
Caspase 3
3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
Cell Survival
Adenosine Triphosphate
Checkpoint Kinase 1
Bendamustine Hydrochloride
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Landau, H. J., McNeely, S. C., Nair, J. S., Comenzo, R. L., Asai, T., Friedman, H., ... Schwartz, G. K. (2012). The checkpoint kinase inhibitor AZD7762 potentiates chemotherapy-induced apoptosis of p53-mutated multiple myeloma cells. Molecular Cancer Therapeutics, 11(8), 1781-1788. https://doi.org/10.1158/1535-7163.MCT-11-0949

The checkpoint kinase inhibitor AZD7762 potentiates chemotherapy-induced apoptosis of p53-mutated multiple myeloma cells. / Landau, Heather J.; McNeely, Samuel C.; Nair, Jayasree S.; Comenzo, Raymond L.; Asai, Takashi; Friedman, Hillel; Jhanwar, Suresh C.; Nimer, Stephen D; Schwartz, Gary K.

In: Molecular Cancer Therapeutics, Vol. 11, No. 8, 01.08.2012, p. 1781-1788.

Research output: Contribution to journalArticle

Landau, HJ, McNeely, SC, Nair, JS, Comenzo, RL, Asai, T, Friedman, H, Jhanwar, SC, Nimer, SD & Schwartz, GK 2012, 'The checkpoint kinase inhibitor AZD7762 potentiates chemotherapy-induced apoptosis of p53-mutated multiple myeloma cells', Molecular Cancer Therapeutics, vol. 11, no. 8, pp. 1781-1788. https://doi.org/10.1158/1535-7163.MCT-11-0949
Landau, Heather J. ; McNeely, Samuel C. ; Nair, Jayasree S. ; Comenzo, Raymond L. ; Asai, Takashi ; Friedman, Hillel ; Jhanwar, Suresh C. ; Nimer, Stephen D ; Schwartz, Gary K. / The checkpoint kinase inhibitor AZD7762 potentiates chemotherapy-induced apoptosis of p53-mutated multiple myeloma cells. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 8. pp. 1781-1788.
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