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

Chen, Chun; Zhuang, Yingting; Chen, Xianling; Chen, Xiaole; Ding, Li; Fan, Yingjuan; Xu, Jianhua; Chen, Yuanzhong; Wu, Lixian

doi:10.18632/oncotarget.14324

Cited by 4 publications

(2 citation statements)

References 35 publications

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“…17‐AAG and cisplatin was another effective combined inhibitor of Hsp90 chaperone function in Bcr‐Abl‐positive human leukemia cells that contained imatinib‐resistant CML cells. The combination can act synergistically, but not antagonistically, on those cells (Chen et al., ).…”

Section: ‐Aag In Preclinical Research: Focus On Combination Therapymentioning

confidence: 99%

Spotlight on 17‐AAG as an Hsp90 inhibitor for molecular targeted cancer treatment

et al. 2019

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Hsp90 is a ubiquitous chaperone with important roles in the organization and maturation of client proteins that are involved in the progression and survival of cancer cells. Multiple oncogenic pathways can be affected by inhibition of Hsp90 function through degradation of its client proteins. That makes Hsp90 a therapeutic target for cancer treatment. 17‐allylamino‐17‐demethoxy‐geldanamycin (17‐AAG) is a potent Hsp90 inhibitor that binds to Hsp90 and inhibits its chaperoning function, which results in the degradation of Hsp90's client proteins. There have been several preclinical studies of 17‐AAG as a single agent or in combination with other anticancer agents for a wide range of human cancers. Data from various phases of clinical trials show that 17‐AAG can be given safely at biologically active dosages with mild toxicity. Even though 17‐AAG has suitable pharmacological potency, its low water solubility and high hepatotoxicity could significantly restrict its clinical use. Nanomaterials‐based drug delivery carriers may overcome these drawbacks. In this paper, we review preclinical and clinical research on 17‐AAG as a single agent and in combination with other anticancer agents. In addition, we highlight the potential of using nanocarriers and nanocombination therapy to improve therapeutic effects of 17‐AAG.

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Section: ‐Aag In Preclinical Research: Focus On Combination Therapymentioning

confidence: 99%

Spotlight on 17‐AAG as an Hsp90 inhibitor for molecular targeted cancer treatment

et al. 2019

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“…One of the major drawbacks of the N-terminal domain inhibitor of HSP90 was the induction of heat shock response [ 55 , 56 , 57 ] and this may be the reason for failure in clinical trials. Further, HSP90 inhibitors targeting the C-terminal domain [ 58 ] have shown promising results and do not lead to induction of heat shock response.…”

Section: Discussionmentioning

confidence: 99%

A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins

Nirgude

Ravindran

et al. 2023

Molecules

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Despite several treatment options for blood cancer, mortality remains high due to relapse and the disease’s aggressive nature. Elevated levels of HSP90, a molecular chaperone essential for protein folding, are associated with poor prognosis in leukemia and lymphoma. HSP90 as a target for chemotherapy has been met with limited success due to toxicity and induction of heat shock. This study tested the activity of an HSP90 inhibitor, SP11, against leukemic cells, mouse lymphoma allograft, and xenograft models. SP11 induced cytotoxicity in vitro in leukemic cell lines and induced cell death via apoptosis, with minimal effect on normal cells. SP11 induced cell death by altering the status of HSP90 client proteins both in vitro and in vivo. SP11 reduced the tumor burden in allograft and xenograft mouse models without apparent toxicity. The half-life of SP11 in the plasma was approximately 2 h. SP11 binding was observed at both the N-terminal and C-terminal domains of HSP90. C-terminal binding was more potent than N-terminal binding of HSP90 in silico and in vitro using isothermal calorimetry. SP11 bioavailability and minimal toxicity in vivo make it a potential candidate to be developed as a novel anticancer agent.

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Unraveling survivin expression in chronic myeloid leukemia: Molecular interactions and clinical implications

et al. 2020

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

Cited by 4 publications

References 35 publications

Spotlight on 17‐AAG as an Hsp90 inhibitor for molecular targeted cancer treatment

Spotlight on 17‐AAG as an Hsp90 inhibitor for molecular targeted cancer treatment

A Coumarin–Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins

Unraveling survivin expression in chronic myeloid leukemia: Molecular interactions and clinical implications

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