P-Glycoprotein–Mediated Resistance to Hsp90-Directed Therapy Is Eclipsed by the Heat Shock Response

McCollum, Andrea K.; TenEyck, Cynthia J.; Stensgard, Bridget; Morlan, Bruce W.; Ballman, Karla V.; Jenkins, Robert B.; Toft, David O.; Erlichman, Charles

doi:10.1158/0008-5472.can-07-5175

Cited by 68 publications

(58 citation statements)

References 50 publications

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“…18,32,29 It is important to emphasize that Hsp70 up-regulation results in resistance to Hsp90 inhibitors, not sensitization. 40,41 In our study Hsp70 was up-regulated after tanespimycin administration in blasts from 83% of patients. However, this Hsp70 up-regulation sometimes occurred before administration of tanespimycin (day 3, Figures 2B and 2D), possibly reflecting cytarabine-induced stress.…”

Section: Discussionmentioning

confidence: 49%

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Kaufmann¹,

Karp²,

Litzow³

et al. 2011

Haematologica

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BackgroundIn preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced downregulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia. Design and MethodsPatients received cytarabine 400 mg/m 2 /day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients. ResultsTwenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m 2 /day for 5 days along with tanespimycin 300 mg/m 2 on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest. ConclusionsBecause exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine. (Clinicaltrials.gov identifier: NCT00098423).

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Section: Discussionmentioning

confidence: 49%

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Kaufmann¹,

Karp²,

Litzow³

et al. 2011

Haematologica

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“…The related quinone reductase NQO2 can also reduce 17AAG to 17AAGH 2 in cell-free studies using rhNQO2 and nicotinamide riboside (Siegel et al, 2007); however, at present there are no data in cellular systems demonstrating a role for NQO2 in the reduction of 17AAG. Other factors include the level of expression of drug transporters such as multi-drug resistance 1 and p-glycoprotein as well as the compensatory induction of heat shock proteins including Hsp27 and Hsp70, which all have been linked to resistance to 17AAG (McCollum et al, 2006(McCollum et al, , 2008Zhang et al, 2010). The role of Hsp90 oncogenic client proteins in stimulating cell proliferation is also an important determinant of tumor sensitivity to Hsp90 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Role for NAD(P)H:quinone Oxidoreductase 1 and Manganese-Dependent Superoxide Dismutase in 17-(Allylamino)-17-demethoxygeldanamycin-Induced Heat Shock Protein 90 Inhibition in Pancreatic Cancer Cells

Siegel¹,

Shieh²,

Yan³

et al. 2010

J Pharmacol Exp Ther

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Previous work demonstrated that NAD(P)H:quinone oxidoreductase 1 (NQO1) metabolized the heat shock protein 90 (Hsp90) inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17AAG) to the corresponding hydroquinone (17AAGH 2 ). The formation of 17AAGH 2 by NQO1 results in a molecule that binds with greater affinity to Hsp90 compared with the parent quinone. 17AAG induced substantial growth inhibition in human pancreatic cancer cell lines expressing NQO1. Growth inhibition induced by 17AAG could be reduced by pretreatment with 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]-indole-4,7-dione (ES936), a mechanism-based inhibitor of NQO1. After treatment with 17AAG, biomarkers of Hsp90 inhibition, including markers of cell-cycle arrest, were more pronounced in NQO1-expressing cells compared with NQO1-null cells. The intracellular concentrations of 17AAG and 17AAGH 2 were measured in human pancreatic cancer cells, and it was observed that larger amounts of 17AAG and 17AAGH 2 could be detected in cells with catalytically active NQO1 compared with cells lacking NQO1 activity or cells pretreated with ES936. These data demonstrate that, in addition to generating an inhibitor with greater affinity for Hsp90 (17AAGH 2 ), reduction of 17AAG to 17AAGH 2 by NQO1 leads to substantially greater intracellular concentrations of 17AAG and 17AAGH 2 . In addition, oxidation of 17AAGH 2 could be prevented by superoxide dismutase (SOD), demonstrating that 17AAGH 2 was sensitive to oxidation by superoxide. Stable transfection of manganese-dependent SOD into MiaPaCa-2 cells resulted in a significantly greater intracellular concentration of 17AAGH 2 with a corresponding increase in growth inhibitory activity. These data confirm the role of NQO1 in sensitivity to 17AAG and demonstrate that SOD functions in conjunction with NQO1 to maintain intracellular levels of 17AAGH 2 , the active Hsp90 inhibitor derived from 17AAG.

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“…P-glycoprotein is known to be involved in cancer cell resistance to many chemotherapeutic agents [10]. Several studies have also shown that P-glycoprotein was involved in the resistance of tumor cells to geldanamycin or its derivatives [11,12].…”

Section: Introductionmentioning

confidence: 99%

Multiple Kinase Pathways Involved in the Different De Novo Sensitivity of Pancreatic Cancer Cell Lines to 17-AAG

Li¹,

Zhang²,

Chen³

et al. 2012

Journal of Surgical Research

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P-Glycoprotein–Mediated Resistance to Hsp90-Directed Therapy Is Eclipsed by the Heat Shock Response

Cited by 68 publications

References 50 publications

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia

Role for NAD(P)H:quinone Oxidoreductase 1 and Manganese-Dependent Superoxide Dismutase in 17-(Allylamino)-17-demethoxygeldanamycin-Induced Heat Shock Protein 90 Inhibition in Pancreatic Cancer Cells

Multiple Kinase Pathways Involved in the Different De Novo Sensitivity of Pancreatic Cancer Cell Lines to 17-AAG

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