Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines

Barnes, David; De, Surya K.; Hensbergen, P van; Moravcsik, Eva; Melo, Junia V.

doi:10.1038/sj.leu.2404533

Cited by 16 publications

(11 citation statements)

References 32 publications

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“…Two recent frontiers in leukemia research are the emergence of imatinib-resistant CMLs [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77] and the discovery of mutations at the Jak2 kinase in certain myeloproliferative diseases. These topic areas document the importance of genetic approaches in leukemia and abnormal hematopoiesis research as they were discovered upon identification of the genetic mutations responsible for the hematopoietic neoplasia.…”

Section: Novel Hematopoietic Targets and Resistancementioning

confidence: 99%

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

et al. 2008

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Section: Novel Hematopoietic Targets and Resistancementioning

confidence: 99%

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

et al. 2008

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“…3 A). Crkl and Grb2 are known as adaptor proteins in p210Bcr‐Abl complexes also including Bcr‐Abl itself [26,27], one of Hsp90 clients that can be degraded by Hsp90 inhibitor [28,29]. Here, we found SNX‐2112 could lower expression of Bcr‐Abl to almost undetectable levels (Fig.…”

Section: Resultsmentioning

confidence: 55%

Transcriptomic and proteomic approach to studying SNX‐2112‐induced K562 cells apoptosis and anti‐leukemia activity in K562‐NOD/SCID mice

et al. 2009

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a b s t r a c t SNX-2112, a novel inhibitor of Hsp90 currently used as an anti-tumor drug, induces apoptosis in multiple tumor cell lines. It destabilizes specific client proteins, but the molecular mechanism of the apoptosis effect of SNX-2112 is poorly understood. Here, we analyzed the apoptotic effect of SNX-2112 on human chronic myeloid leukemia (CML) K562 cells. Transcriptomic and proteomic approaches further revealed that caspase signals originated from mitochondria dysfunction, mediated by Akt signaling pathway inactivity. Additionally, SNX-2112 prolonged the survival time of NOD/SCID mice inoculated with K562 tumor cells. Our results demonstrated the therapeutic potential of SNX-2112 against human CML. Structured summary:MINT-7033976: BAD (uniprotkb:Q92934) physically interacts (MI:0218) with Bcl2-Xl (uniprotkb:Q07817) by anti bait coimmunoprecipitation (MI:0006)

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“…Hsp90 affects the maturation and stability of Bcr-Abl by chaperone function. Bcr-Abl point mutants isolated from patients with imatinib mesylate–resistant CML remain sensitive to Hsp90 inhibitors [34, 35]. Our results indicate 17-AAG+CP synergistically reduced the amounts of Hsp90 that were coprecipitated with Bcr-Abl, resulting in overcoming imatinib resistance.…”

Section: Discussionmentioning

confidence: 80%

Hsp90 N- and C-terminal double inhibition synergistically suppresses Bcr-Abl-positive human leukemia cells

et al. 2016

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Heat shock protein 90 (Hsp90) contains amino (N)–terminal domain, carboxyl(C)-terminal domain, and middle domains, which activate Hsp90 chaperone function cooperatively in tumor cells. One terminal occupancy might influence another terminal binding with inhibitor. The Bcr-Abl kinase is one of the Hsp90 clients implicated in the pathogenesis of chronic myeloid leukemia (CML). Present studies demonstrate that double inhibition of the N- and C-terminal termini can disrupt Hsp90 chaperone function synergistically, but not antagonistically, in Bcr-Abl-positive human leukemia cells. Furthermore, both the N-terminal inhibitor 17-AAG and the C-terminal inhibitor cisplatin (CP) have the capacity to suppress progenitor cells; however, only CP is able to inhibit leukemia stem cells (LSCs) significantly, which implies that the combinational treatment is able to suppress human leukemia in different mature states.

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Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines

Cited by 16 publications

References 32 publications

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

Transcriptomic and proteomic approach to studying SNX‐2112‐induced K562 cells apoptosis and anti‐leukemia activity in K562‐NOD/SCID mice

Hsp90 N- and C-terminal double inhibition synergistically suppresses Bcr-Abl-positive human leukemia cells

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