Oncotarget

Research Papers:

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

Kimberley L. Kaufman _, Yiping Jenkins, Munther Alomari, Mehdi Mirzaei, O.Giles Best, Dana Pascovici, Swetlana Mactier, Stephen P. Mulligan, Paul A. A. Haynes and Richard I. Christopherson

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Oncotarget. 2015; 6:40981-40997. https://doi.org/10.18632/oncotarget.5715

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Abstract

Kimberley L. Kaufman1,2,*, Yiping Jenkins1,*, Munther Alomari1, Mehdi Mirzaei3, O. Giles Best4, Dana Pascovici5, Swetlana Mactier1, Stephen P. Mulligan4, Paul A. Haynes3, Richard I. Christopherson1

1School of Molecular Bioscience, University of Sydney, Darlington, NSW 2006, Australia

2Molecular Neuropathology, Brain and Mind Centre, Camperdown, NSW 2050, Australia

3Department of Chemistry and Biomolecular Sciences, Macquarie University, North Ryde, NSW 2109, Australia

4Northern Blood Research Centre, Kolling Institute for Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia

5Australian Proteome Analysis Facility, Macquarie University, North Ryde, NSW 2109, Australia

*These authors have contributed equally to this work

Correspondence to:

Richard I. Christopherson, e-mail: richard.christopherson@sydney.edu.au

Keywords: chronic lymphocytic leukemia (CLL), fludarabine nucleoside, Hsp90 inhibitor, MYC, NFkB2

Received: August 02, 2015     Accepted: September 16, 2015     Published: November 06, 2015

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.


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