The Hsp90 inhibitor SNX-7081 is synergistic with fludarabine nucleoside via DNA damage and repair mechanisms in human, p53-negative chronic lymphocytic leukemia

K. L. Kaufman, Y. Jenkins, M. Alomari, M. Mirzaei, O. Giles Best, D. Pascovici, S. Mactier, S. P. Mulligan, P. A. Haynes, R. I. Christopherson

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Clinical trials of heat shock protein 90 (Hsp90) inhibitors have been limited by high toxicity. We previously showed that the Hsp90 inhibitor, SNX-7081, synergizes with and restores sensitivity to fludarabine nucleoside (2-FaraA) in human chronic lymphocytic leukemia (CLL) cells with lesions in the p53 pathway (Best OG, et al., Leukemia Lymphoma 53:1367-75, 2012). Here, we used label-free quantitative shotgun proteomics and comprehensive bioinformatic analysis to determine the mechanism of this synergy. We propose that 2-FaraA-induced DNA damage is compounded by SNX-7081-mediated inhibition of DNA repair, resulting in enhanced induction of apoptosis. DNA damage responses are impaired in part due to reductions in checkpoint regulators BRCA1 and cyclin D1, and cell death is triggered following reductions of MYC and nucleolin and an accumulation of apoptosis-inducing NFkB2 p100 subunit. Loss of nucleolin can activate Fas-mediated apoptosis, leading to the increase of pro-apoptotic proteins (BID, fas-associated factor-2) and subsequent apoptosis of p53-negative, 2-FaraA refractory CLL cells. A significant induction of DNA damage, indicated by increases in DNA damage marker γH2AX, was observed following the dual drug treatment of additional cell lines, indicating that a similar mechanism may operate in other p53-mutated human B-lymphoid cancers. These results provide valuable insight into the synergistic mechanism between SNX-7081 and 2-FaraA that may provide an alternative treatment for CLL patients with p53 mutations, for whom therapeutic options are currently limited. Moreover, this drug combination reduces the effective dose of the Hsp90 inhibitor and may therefore alleviate any toxicity encountered.
Original languageEnglish
Pages (from-to)40981-40997
Number of pages17
JournalOncotarget
Volume6
Issue number38
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • Antineoplastic Agents/pharmacology Apoptosis/drug effects BRCA1 Protein/metabolism Benzamides/*pharmacology Blotting, Western Cell Line, Tumor Chromatography, Liquid/methods Cyclin D1/metabolism *DNA Damage DNA Repair/*drug effects Drug Synergism HSP90 Heat-Shock Proteins/*antagonists & inhibitors/metabolism Humans Leukemia, Lymphocytic, Chronic, B-Cell/genetics/metabolism/pathology Mutation NF-kappa B p52 Subunit/metabolism Phosphoproteins/metabolism Protein Interaction Maps/drug effects Proteomics/methods Proto-Oncogene Proteins c-myc/metabolism RNA-Binding Proteins/metabolism Signal Transduction/drug effects/genetics Tandem Mass Spectrometry Tumor Suppressor Protein p53/genetics/*metabolism Vidarabine/*analogs & derivatives/pharmacology Hsp90 inhibitor Myc NFkB2 chronic lymphocytic leukemia (CLL) fludarabine nucleoside
  • Hsp90 inhibitor
  • MYC
  • Chronic lymphocytic leukemia (CLL)
  • Fludarabine nucleoside
  • NFkB2

Fingerprint

Dive into the research topics of 'The Hsp90 inhibitor SNX-7081 is synergistic with fludarabine nucleoside via DNA damage and repair mechanisms in human, p53-negative chronic lymphocytic leukemia'. Together they form a unique fingerprint.

Cite this