Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage

Barker, Catherine R.; McNamara, A.; Rackstraw, Stephen A.; Nelson, David E.; White, Mike; Watson, Alastair; Jenkins, Jennifer

doi:10.1093/nar/gkj516

Cited by 34 publications

(20 citation statements)

References 24 publications

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“…Barker et al recently demonstrated that inhibition of heat shock protein 90 (Hsp90) with geldanamycin disrupts the Hsp90-topo II interaction leading to an increase of unbound topo II. In the presence of a topo II poison the elevated unbound topo II levels resulted in an increase in cleavable complexes and a corresponding increase in DNA damage and cell death (25). Similarly, in the present study, we demonstrate that when a topo II poison is present, increased levels of enzymatically active topo II protein results in increased DNA damage and increased cell death.…”

Section: Discussionsupporting

confidence: 82%

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Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Congdon

Pourpak

Escalante

et al. 2008

Biochemical Pharmacology

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Multiple myeloma (MM) is an incurable malignancy of plasma cells. Although multiple myeloma patients often respond to initial therapy, the majority of patients will relapse with disease that is refractory to further drug treatment. Thus, new therapeutic strategies are needed. One common mechanism of acquired drug resistance involves a reduction in the expression or function of the drug target. We hypothesized that the cytotoxic activity of topoisomerase II (topo II) poisons could be enhanced, and drug resistance overcome, by increasing the expression and activity of the drug target, topo II in myeloma cells. To test this hypothesis, we evaluated the cytotoxicity of the anthracenecontaining topo II poison, ethonafide (AMP-53/6-ethoxyazonafide), in combination with the proteasome inhibitor bortezomib (PS-341/Velcade). Combination drug activity studies were done in 8226/S myeloma cells and its drug resistant subclone, 8226/Dox1V. We found that a 24-hour treatment of cells with bortezomib maximally increased topo IIα protein expression and activity, and consistently increased the cytotoxicity of ethonafide in the 8226/S and 8226/Dox1V cell lines. This increase in cytotoxicity corresponded to an increase in DNA double-strand breaks, as measured by the neutral comet assay. Therefore, increasing topo IIα expression through inhibition of proteasomal degradation increased DNA double-strand breaks and enhanced the cytotoxicity of the topo II poison ethonafide. These data suggest that bortezomib-mediated stabilization of topo IIα expression may potentiate the cytotoxic activity of topo II poisons and thereby, provide a strategy to circumvent drug resistance.

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Section: Discussionsupporting

confidence: 82%

“…Increasing the expression and activity of topoisomerase as a strategy to enhance topo II poison efficacy has been the subject of ongoing studies (25). Barker et al recently demonstrated that inhibition of heat shock protein 90 (Hsp90) with geldanamycin disrupts the Hsp90-topo II interaction leading to an increase of unbound topo II.…”

Section: Discussionmentioning

confidence: 99%

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Congdon

Pourpak

Escalante

et al. 2008

Biochemical Pharmacology

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“…It is reasonable to suggest that the genotoxic stress induced by aberrant entry into mitosis with unrepaired DNA damage was sufficient to account for the increased cell death observed following combination ganetespib-doxorubicin exposure. Of interest, doxorubicin also functions as a topoisomerase II inhibitor and HSP90 blockade can enhance the activity of such poisons through disruption of a protective HSP90-topoisomerase II complex (40,41). Furthermore, the doxorubicin-cyclophosphamide doublet forms the basis of most systemic TNBC therapies and the addition of ganetespib to this regimen conferred superior efficacy in MDA-MB-231 xenografts.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Activity Profile and Therapeutic Efficacy of the HSP90 Inhibitor Ganetespib in Triple-Negative Breast Cancer

Proia

Zhang

Sequeira

et al. 2014

Clinical Cancer Research

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Purpose: Treatment options for patients with triple-negative breast cancer (TNBC) are largely limited to systemic chemotherapies, which have shown disappointing efficacy in the metastatic setting. Here, we undertook a comprehensive evaluation of the activity of ganetespib, a potent inhibitor of HSP90, in this malignancy.Experimental Design: The antitumor and antimetastatic activity of ganetespib was investigated using TNBC cell lines and xenograft models. Combinatorial drug analyses were performed with chemotherapeutic agents and concomitant effects on DNA damage and cell-cycle disruption were assessed in vitro; antitumor efficacy was assessed in vivo. Metabolic and objective tumor responses were evaluated in patients with metastatic TNBC undergoing ganetespib treatment.Results: Ganetespib simultaneously deactivated multiple oncogenic pathways to potently reduce cell viability in TNBC cell lines, and suppressed lung metastases in experimental models. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin-cyclophosphamide regimen in TNBC xenografts. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung and lymphatic lesions were seen in patients on ganetespib monotherapy.Conclusion: The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC. Clin Cancer Res; 20(2); 413-24. Ó2013 AACR.

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“…To determinate whether drug inhibits topo II without drug-adducted DNA [28], 2 µg of nuclear extract (4 µl) was incubated with drug for 20′ on ice, then this reaction was incubated with 50 ng kDNA (2 µl) in the presence of topo II assay buffer (1 µl). Reactions were stopped by addition of 1/5 stop buffer/gel loading dye (5% Sarkosil, 0.125% bromophenol blue, 25% glycerol) and digest with 50 µg/ml of proteinase K for 30 min at 37°C.…”

Section: Decatenation Assaymentioning

confidence: 99%

Characterization of the cell growth inhibitory effects of a novel DNA-intercalating bipyridyl-thiourea-Pt(II) complex in cisplatin-sensitive and—resistant human ovarian cancer cells

et al. 2009

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The cellular effects of a novel DNA-intercalating agent, the bipyridyl complex of platinum(II) with diphenyl thiourea, [Pt(bipy)(Ph(2)-tu)(2)]Cl(2), has been analyzed in the cisplatin (cDDP)-sensitive human ovarian carcinoma cell line, 2008, and its -resistant variant, C13* cells, in which the highest accumulation and cytotoxicity was found among six related bipyridyl thiourea complexes. We also show here that this complex causes reactive oxygen species to form and inhibits topoisomerase II activity to a greater extent in the sensitive than in the resistant line. The impairment of this enzyme led to DNA damage, as shown by the comet assay. As a consequence, cell cycle distribution has also been greatly perturbed in both lines. Morphological analysis revealed deep cellular derangement with the presence of cellular masses, together with increased membrane permeability and depolarization of the mitochondrial membrane. Some of these effects, sometimes differentially evident between the two cell lines, might also be related to the decrease of total cell magnesium content caused by this thiourea complex both in sensitive and resistant cells, though the basal content of this ion was higher in the cDDP-resistant line. Altogether these results suggest that this compound exerts its cytotoxicity by mechanisms partly mediated by the resistance phenotype. In particular, cDDP-sensitive cells were affected mostly by impairing topoisomerase II activity and by increasing membrane permeability and the formation of reactive oxygen species; conversely, mitochondrial impairment appeared to play the most important role in the action of complex F in resistant cells.

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Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage

Cited by 34 publications

References 24 publications

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Preclinical Activity Profile and Therapeutic Efficacy of the HSP90 Inhibitor Ganetespib in Triple-Negative Breast Cancer

Characterization of the cell growth inhibitory effects of a novel DNA-intercalating bipyridyl-thiourea-Pt(II) complex in cisplatin-sensitive and—resistant human ovarian cancer cells

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