The Hsp90 inhibitor SNX-7081 synergizes with and restores sensitivity to fludarabine in chronic lymphocytic leukemia cells with lesions in the TP53 pathway: a potential treatment strategy for fludarabine refractory disease: Leuk Lymphoma

O. G. Best; Y. Che; N. Singh; C. Forsyth; R. I. Christopherson; S. P. Mulligan

doi:10.3109/10428194.2011.647310

The Hsp90 inhibitor SNX-7081 synergizes with and restores sensitivity to fludarabine in chronic lymphocytic leukemia cells with lesions in the TP53 pathway: a potential treatment strategy for fludarabine refractory disease: Leuk Lymphoma

O. G. Best, Y. Che, N. Singh, C. Forsyth, R. I. Christopherson, S. P. Mulligan

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

Drug resistance in chronic lymphocytic leukemia (CLL) associated with lesions in the ATM/TP53 pathway represents a major challenge in clinical management. Evidence suggests that heat shock protein-90 (Hsp90) inhibitors may represent a therapeutic option in combination with more conventional therapies. We explored the effects of combining the Hsp90 inhibitor, SNX-7081, with fludarabine in vitro against CLL cells and hematological cell lines. In seven cell lines and 23 patient samples synergy between SNX-7081 and fludarabine (2-FaraA) was apparent in the three TP53 mutated cell lines and at significantly lower concentrations in TP53 or ATM dysfunctional patient cells. In 11/13 2-FaraA-resistant patient samples, SNX-7081 reduced the 50% inhibitory concentration to within a clinically achievable range. Synergy between SNX-7081 and 2-FaraA was evident in both the cell lines and patient samples as a significant decrease in cell viability. Our data suggest that combining SNX-7081 and fludarabine may be effective in the treatment of fludarabine-refractory CLL.

Original language	English
Pages (from-to)	1367-1375
Number of pages	9
Journal	Leukemia & lymphoma
Volume	53
Issue number	7
DOIs	https://doi.org/10.3109/10428194.2011.647310
Publication status	Published - 2012
Externally published	Yes

Keywords

Antineoplastic Agents/pharmacology Apoptosis/drug effects Ataxia Telangiectasia Mutated Proteins Benzamides/*pharmacology Cell Cycle/drug effects Cell Cycle Proteins/genetics/metabolism Cell Line Cell Line, Tumor Cell Survival/drug effects DNA-Binding Proteins/genetics/metabolism Dose-Response Relationship, Drug Drug Resistance, Neoplasm/drug effects Drug Synergism Flow Cytometry HL-60 Cells HSP90 Heat-Shock Proteins/antagonists & inhibitors Humans Leukemia, Lymphocytic, Chronic, B-Cell/genetics/metabolism/pathology Mutation Protein-Serine-Threonine Kinases/genetics/metabolism Signal Transduction/*drug effects Tumor Cells, Cultured Tumor Suppressor Protein p53/genetics/*metabolism Tumor Suppressor Proteins/genetics/metabolism Vidarabine/*analogs & derivatives/pharmacology

Access to Document

10.3109/10428194.2011.647310Licence: In Copyright

Fingerprint

Dive into the research topics of 'The Hsp90 inhibitor SNX-7081 synergizes with and restores sensitivity to fludarabine in chronic lymphocytic leukemia cells with lesions in the TP53 pathway: a potential treatment strategy for fludarabine refractory disease: Leuk Lymphoma'. Together they form a unique fingerprint.

Cite this

Best, O. G., Che, Y., Singh, N., Forsyth, C., Christopherson, R. I., & Mulligan, S. P. (2012). The Hsp90 inhibitor SNX-7081 synergizes with and restores sensitivity to fludarabine in chronic lymphocytic leukemia cells with lesions in the TP53 pathway: a potential treatment strategy for fludarabine refractory disease: Leuk Lymphoma. Leukemia & lymphoma, 53(7), 1367-1375. https://doi.org/10.3109/10428194.2011.647310

@article{5969af5a858d41a39cc7df322a6335dc,

title = "The Hsp90 inhibitor SNX-7081 synergizes with and restores sensitivity to fludarabine in chronic lymphocytic leukemia cells with lesions in the TP53 pathway: a potential treatment strategy for fludarabine refractory disease: Leuk Lymphoma",

abstract = "Drug resistance in chronic lymphocytic leukemia (CLL) associated with lesions in the ATM/TP53 pathway represents a major challenge in clinical management. Evidence suggests that heat shock protein-90 (Hsp90) inhibitors may represent a therapeutic option in combination with more conventional therapies. We explored the effects of combining the Hsp90 inhibitor, SNX-7081, with fludarabine in vitro against CLL cells and hematological cell lines. In seven cell lines and 23 patient samples synergy between SNX-7081 and fludarabine (2-FaraA) was apparent in the three TP53 mutated cell lines and at significantly lower concentrations in TP53 or ATM dysfunctional patient cells. In 11/13 2-FaraA-resistant patient samples, SNX-7081 reduced the 50% inhibitory concentration to within a clinically achievable range. Synergy between SNX-7081 and 2-FaraA was evident in both the cell lines and patient samples as a significant decrease in cell viability. Our data suggest that combining SNX-7081 and fludarabine may be effective in the treatment of fludarabine-refractory CLL.",

keywords = "Antineoplastic Agents/pharmacology Apoptosis/drug effects Ataxia Telangiectasia Mutated Proteins Benzamides/*pharmacology Cell Cycle/drug effects Cell Cycle Proteins/genetics/metabolism Cell Line Cell Line, Tumor Cell Survival/drug effects DNA-Binding Proteins/genetics/metabolism Dose-Response Relationship, Drug Drug Resistance, Neoplasm/drug effects Drug Synergism Flow Cytometry HL-60 Cells HSP90 Heat-Shock Proteins/antagonists & inhibitors Humans Leukemia, Lymphocytic, Chronic, B-Cell/genetics/metabolism/pathology Mutation Protein-Serine-Threonine Kinases/genetics/metabolism Signal Transduction/*drug effects Tumor Cells, Cultured Tumor Suppressor Protein p53/genetics/*metabolism Tumor Suppressor Proteins/genetics/metabolism Vidarabine/*analogs & derivatives/pharmacology",

author = "Best, {O. G.} and Y. Che and N. Singh and C. Forsyth and Christopherson, {R. I.} and Mulligan, {S. P.}",

year = "2012",

doi = "10.3109/10428194.2011.647310",

language = "English",

volume = "53",

pages = "1367--1375",

journal = "Leukemia & lymphoma",

issn = "1026-8022",

number = "7",

}

Best, OG, Che, Y, Singh, N, Forsyth, C, Christopherson, RI & Mulligan, SP 2012, 'The Hsp90 inhibitor SNX-7081 synergizes with and restores sensitivity to fludarabine in chronic lymphocytic leukemia cells with lesions in the TP53 pathway: a potential treatment strategy for fludarabine refractory disease: Leuk Lymphoma', Leukemia & lymphoma, vol. 53, no. 7, pp. 1367-1375. https://doi.org/10.3109/10428194.2011.647310

The Hsp90 inhibitor SNX-7081 synergizes with and restores sensitivity to fludarabine in chronic lymphocytic leukemia cells with lesions in the TP53 pathway: a potential treatment strategy for fludarabine refractory disease: Leuk Lymphoma. / Best, O. G.; Che, Y.; Singh, N. et al.
In: Leukemia & lymphoma, Vol. 53, No. 7, 2012, p. 1367-1375.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - The Hsp90 inhibitor SNX-7081 synergizes with and restores sensitivity to fludarabine in chronic lymphocytic leukemia cells with lesions in the TP53 pathway: a potential treatment strategy for fludarabine refractory disease

T2 - Leuk Lymphoma

AU - Best, O. G.

AU - Che, Y.

AU - Singh, N.

AU - Forsyth, C.

AU - Christopherson, R. I.

AU - Mulligan, S. P.

PY - 2012

Y1 - 2012

N2 - Drug resistance in chronic lymphocytic leukemia (CLL) associated with lesions in the ATM/TP53 pathway represents a major challenge in clinical management. Evidence suggests that heat shock protein-90 (Hsp90) inhibitors may represent a therapeutic option in combination with more conventional therapies. We explored the effects of combining the Hsp90 inhibitor, SNX-7081, with fludarabine in vitro against CLL cells and hematological cell lines. In seven cell lines and 23 patient samples synergy between SNX-7081 and fludarabine (2-FaraA) was apparent in the three TP53 mutated cell lines and at significantly lower concentrations in TP53 or ATM dysfunctional patient cells. In 11/13 2-FaraA-resistant patient samples, SNX-7081 reduced the 50% inhibitory concentration to within a clinically achievable range. Synergy between SNX-7081 and 2-FaraA was evident in both the cell lines and patient samples as a significant decrease in cell viability. Our data suggest that combining SNX-7081 and fludarabine may be effective in the treatment of fludarabine-refractory CLL.

AB - Drug resistance in chronic lymphocytic leukemia (CLL) associated with lesions in the ATM/TP53 pathway represents a major challenge in clinical management. Evidence suggests that heat shock protein-90 (Hsp90) inhibitors may represent a therapeutic option in combination with more conventional therapies. We explored the effects of combining the Hsp90 inhibitor, SNX-7081, with fludarabine in vitro against CLL cells and hematological cell lines. In seven cell lines and 23 patient samples synergy between SNX-7081 and fludarabine (2-FaraA) was apparent in the three TP53 mutated cell lines and at significantly lower concentrations in TP53 or ATM dysfunctional patient cells. In 11/13 2-FaraA-resistant patient samples, SNX-7081 reduced the 50% inhibitory concentration to within a clinically achievable range. Synergy between SNX-7081 and 2-FaraA was evident in both the cell lines and patient samples as a significant decrease in cell viability. Our data suggest that combining SNX-7081 and fludarabine may be effective in the treatment of fludarabine-refractory CLL.

KW - Antineoplastic Agents/pharmacology Apoptosis/drug effects Ataxia Telangiectasia Mutated Proteins Benzamides/pharmacology Cell Cycle/drug effects Cell Cycle Proteins/genetics/metabolism Cell Line Cell Line, Tumor Cell Survival/drug effects DNA-Binding Prot

U2 - 10.3109/10428194.2011.647310

DO - 10.3109/10428194.2011.647310

M3 - Article

SN - 1026-8022

VL - 53

SP - 1367

EP - 1375

JO - Leukemia & lymphoma

JF - Leukemia & lymphoma

IS - 7

ER -

Best OG, Che Y, Singh N, Forsyth C, Christopherson RI, Mulligan SP. The Hsp90 inhibitor SNX-7081 synergizes with and restores sensitivity to fludarabine in chronic lymphocytic leukemia cells with lesions in the TP53 pathway: a potential treatment strategy for fludarabine refractory disease: Leuk Lymphoma. Leukemia & lymphoma. 2012;53(7):1367-1375. doi: 10.3109/10428194.2011.647310