Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone

Clarke, Paul A.; Hostein, Isabelle; Banerji, Udai; Stefano, Francesca Di; Maloney, Alison; Walton, Mike I.; Judson, Ian; Workman, Paul

doi:10.1038/sj.onc.1203753

Cited by 179 publications

(151 citation statements)

References 46 publications

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“…8 In this study, we were unable to detect any alteration in genes coding for known Hsp90 client proteins including c-Raf-1, ErbB2, Akt, and cyclin-dependent kinase 4. Similarly, other investigators have found these phenomena in other cancer types (18,19). Interestingly, when we compared our results with a recently published study in ovarian cancer, we found that only the 70 kDa heat shock protein isoforms and eukaryotic translation initiation factor 3 matched between these two tumor types.…”

Section: Discussionsupporting

confidence: 43%

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Song

Chaerkady

Tan

et al. 2008

Molecular Cancer Therapeutics

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Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose-and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.

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Section: Discussionsupporting

confidence: 43%

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Song

Chaerkady

Tan

et al. 2008

Molecular Cancer Therapeutics

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“…Levels of Hsp70 were also increased in the same manner (data not shown). Induction of these two members of the Hsp70 family has been shown to be the most sensitive marker of cellular Hsp90 inhibition (Clarke et al, 2000;Whitesell et al, 2003). No stress response was demonstrated in cells lacking the FLT3 mutation.…”

Section: Hsp90 Inhibition Results In Dephosphorylation Of Stat5 Mapkmentioning

confidence: 99%

Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling

Shaer¹,

Walsby²,

Gilkes³

et al. 2008

Br J Haematol

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SummaryActivating mutations of the FMS-like tyrosine kinase 3 gene (FLT3) occur in approximately one-third of patients with acute myeloid leukaemia (AML) and predict for a poor outcome. Heat shock protein 90 (Hsp90) is a molecular chaperone that is frequently used by cancer cells to stabilise mutant oncoproteins. Mutant FLT3 is chaperoned by Hsp90 in primary AML blasts whereas unmutated FLT3 is not, making Hsp90 inhibitors potentially useful therapeutically. The present study showed that inhibition of Hsp90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) was cytotoxic to primary AML cells expressing mutant FLT3. Inhibition of Hsp90 results in altered downstream signalling effects in primary AML cells with disruption of Janus kinase-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase and phosphatidylinositol 3/AKT signalling pathways. Co-treatment of blasts with 17-AAG and cytarabine resulted in a synergistic or additive effect in approximately 50% of AML cases tested. Our results confirm that Hsp90 is a valid molecular target in the therapy of AML. Inhibition of Hsp90 in parallel with conventional AML therapies may have particular benefit in those patients with the poor prognostic FLT3 mutant disease.Keywords: acute myeloid leukaemia, FLT3, heat shock protein 90, Ara-C, 17-allylamino-17-demethoxygeldanamycin. research paper ª

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“…Cells treated with 17-AAG and examined by microarray had increased mRNA levels of certain multidrug transporters, such as multidrug resistance 1 (MDR1), or MDR-associated protein 1 (35). These transporters, which render cells resistant to a variety of structurally and functionally unrelated antitumor drugs, can bind and transport these drugs out of the cell in an ATP-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of Heat Shock Protein 27 Induces Resistance to 17-Allylamino-Demethoxygeldanamycin through a Glutathione-Mediated Mechanism

McCollum¹,

TenEyck

Sauer³

et al. 2006

Cancer Research

151

152

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Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone

Cited by 179 publications

References 46 publications

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling

Up-regulation of Heat Shock Protein 27 Induces Resistance to 17-Allylamino-Demethoxygeldanamycin through a Glutathione-Mediated Mechanism

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