HSP90 protects apoptotic cleavage of vimentin in geldanamycin-induced apoptosis
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Keywords:
Geldanamycin
Hsp90 inhibitor
Celastrol
Celastrol
Geldanamycin
Natural product
Mechanism of Action
Structure–activity relationship
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Geldanamycin
Hsp90 inhibitor
IC50
Viability assay
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A high-throughput screening of natural product libraries identified (−)-gambogic acid (1), a component of the exudate of Garcinia harburyi, as a potential Hsp90 inhibitor, in addition to the known Hsp90 inhibitor celastrol (2). Subsequent testing established that 1 inhibited cell proliferation, brought about the degradation of Hsp90 client proteins in cultured cells, and induced the expression of Hsp70 and Hsp90, which are hallmarks of Hsp90 inhibition. Gambogic acid also disrupted the interaction of Hsp90, Hsp70, and Cdc37 with the heme-regulated eIF2α kinase (HRI, an Hsp90-dependent client) and blocked the maturation of HRI in vitro. Surface plasmon resonance spectroscopy indicated that 1 bound to the N-terminal domain of Hsp90 with a low micromolar Kd, in a manner that was not competitive with the Hsp90 inhibitor geldanamycin (3). Molecular docking experiments supported the posit that 1 binds Hsp90 at a site distinct from Hsp90s ATP binding pocket. The data obtained have firmly established 1 as a novel Hsp90 inhibitor and have provided evidence of a new site that can be targeted for the development of improved Hsp90 inhibitors.
Geldanamycin
Gambogic acid
Celastrol
Hsp90 inhibitor
Natural product
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OBJECTIVE:To investigate the underlying mechanism of HSP90 suppressing tumor necrosis factor α(TNFα) and cycloheximide(CHX)-induced apoptosis. METHODS:We used electroporation to establish stable HSP90 overexpression clones;using laser confocal microscopy and flowcytometry to observe apoptosis induced by TNF-α/CHX;using Western blotting and immunoprecipitation to show whether HSP90 binds directly with Bid(BH3 interacting death agonist) and monitor the changes of Bid and the function of HSP90’s inhibitor geldanamycin in this event. RESULTS:HSP90 suppressed TNFα/CHX-induced apoptosis in stable HSP90-overexpressing NIH3T3 cells; The mechanism by which HSP90 suppressed TNFα-induced apoptosis was that HSP90 prevented the cleavage of Bid through direct binding with Bid; disrupting the function of HSP90 by the addition of its specific inhibitor,geldanamycin,blocked HSP90’s protection of Bid cleavage. CONCLUSION:The abundant existence of HSP90, even in physiological conditions, plays an important role in preventing cell apoptosis and maintaining cellular homeostasis, not only by promoting protein folding, but also by preventing Bid cleavag and keeping proapoptotic factors in an inert state;one mechanism by which HSP90’s inhibitor acts as an anti-cancer drug could be to promote the release of Bid from the HSP90 complex,and this event promotes cancer cell apoptosis.
Geldanamycin
Hsp90 inhibitor
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Geldanamycin and radicicol, antibiotics produced by Streptomycetes and fungi, respectively, were originally discovered many years ago. Only recently was it discovered that they bind with high specificity within the ADP/ATP binding pocket of the Hsp90 molecular chaperone, thereby inhibiting the function of Hsp90. In eukaryotic cells Hsp90 catalyzes the final activation step of many of the most important regulatory proteins. Cells that lose this function are severely compromised and cannot progress through the cell cycle. In cell-culture systems, the administration of geldanamycin induces degradation of several signal transduction proteins of oncological importance. Hsp90 inhibitors are, therefore, now attracting considerable attention as potential antitumor agents; one geldanamycin derivative is already in phase I trials as an anticancer drug. These drugs may also have virucidal, antimalarial and ischemia-protective effects.
Geldanamycin
Hsp90 inhibitor
Chaperone (clinical)
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HSP90は主要な細胞内分子シャペロンの一つであり,細胞ストレス状況下で発現量が増大するが,通常でも細胞質にもっとも多く存在するタンパク質の一つである.HSP90は様々な細胞内タンパク質と相互作用してその正確なフォルディングと機能を保証する役割を持つ.HSP90と相互作用するクライアントタンパク質にはプロテインキナーゼやステロイドホルモン受容体等の細胞増殖や分化に重要な役割を果たすシグナル伝達分子が多く含まれる.HSP90はCdc37やFKBP52といった他の分子シャペロンと協調しながら,クライアントタンパク質が正しくシグナルに応答して機能する為に必須の因子としてATP依存的に働いている.ゲルダナマイシンはHSP90のATP-bindingポケットに結合してそのシャペロン機能を抑制する特異的な阻害薬であり,HSP90依存性のクライアントタンパク質の不活性化·不安定化と分解を引き起こす.HSP90のクライアントタンパク質には細胞周期·細胞死や細胞の生存·癌化に関わる機能タンパク質が多く含まれ,ゲルダナマイシン処理でHSP90を阻害すると培養癌細胞の増殖が抑制され,また実験動物での腫瘍縮小効果が観察される.ゲルダナマイシンはHSP90という単一のタンパク質に対する特異的な阻害薬でありながら,細胞周期·細胞分裂·細胞生存シグナル·アポトーシス·ステロイドホルモン作用·ストレス耐性などに関わる多面的なクライアント分子を同時に阻害できるという点で,これまでに無く広範でかつ効果的な抗癌作用を持つ薬剤となり得る.ゲルダナマイシンと同様のHSP90阻害効果を持ちながら腎·肝毒性を軽減した誘導体である17-allylaminogeldanamycin(17-AAG)は既にヒトに対するPhaseIの治験を経て,まもなく癌患者に対するPhaseIIの臨床試験が始められようとしている.
Geldanamycin
CDC37
Hsp90 inhibitor
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Geldanamycin
Hsp90 inhibitor
Celastrol
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The heat shock protein Hsp90 has increasingly become an important therapeutic target especially for treatment of cancers. Inhibition of the ATPase activity of Hsp90 by natural products (e.g., 17-allylaminogeldanamycin or radicicol) leads to the ubiquitination of oncogenic client proteins such as Her-2, Raf-1, and p-Akt followed by their proteasomal degradation. Hsp90 inhibitors simultaneously target multiple oncogenic proteins and provide an advantage for cancer therapy due to the potential for increased efficacy and overcoming drug resistance. In an effort to convert geldanamycin into a druglike compound with better pharmacokinetic properties and efficacy in human tumor xenograft models, geldanamycin was derivatized on the 17-position to prepare new analogues such as 17-geldanamycin amides, carbamates, and ureas and 17-arylgeldanamycins. All the compounds were first evaluated ex vivo using a cell-based Her-2 degradation assay and in vitro using biochemical assays that measure recombinant Hsp90 (rHsp90) competitive binding and changes in rHsp90 conformation. In addition, we confirmed the selectivity of geldanamycin analogues for Hsp90 derived from tumor cells using a novel cell lysate binding assay.
Geldanamycin
Hsp90 inhibitor
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Background: Effective drug binding to its specific receptor determines the therapeutic effect. Tumor cells employ Heat Shock Protein 90 (Hsp90) to survive as Hsp90 prevents apoptosis. The protein is the top expressed protein among others. This expression rate further increases in tumor cells and provides a fine target for drug design. However, mutations and copy number variations, single nucleotide polymorphisms of the target gene as well as strong binding of therapeutic agents to the target provide adverse effects. Aims: This work investigates HSP90 interaction with common inhibitor geldanamycin through key mutations to understand possible effects. Methods: In silico analysis by YASARA software was employed to reveal interactions between HSP90 WT and its mutant along with geldanamycin. Results: One key inhibitor-resistant critical residue interaction was monitored for each cytosolic HSP90 isoform. The residues are at critical positions during conformational changes and at the mutated regions of the protein. However, finely designed geldanamycin still tolerates its binding to HSP90. Conclusion: HSP has no introns and may seem non-mutable, but designing inhibitors by considering structural alterations increases the effectiveness of the drug candidates and limits side effects through in silico experiments.
Geldanamycin
Hsp90 inhibitor
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Heat shock proteins (Hsp) are highly conserved proteins and their expression is dependent on the level of various cellular stresses. Hsp work as a molecular chaperon for several cellular proteins and have cytoprotective roles. Their function is essential for normal cell viability and growth. Hsp90 interacts with proteins mediating cell signaling involved in essential processes such as proliferation, cell cycle control, angiogenesis and apoptosis. The naturally occurring Hsp90 inhibitor geldanamycin (GA) was the first to demonstrate anticancer activity but its significant toxicity profile in pre-clinical models precluded its clinical development. Subsequent, several Hsp90 inhibitors have been developed and underwent clinical development with favorable safety profiles. Several initial clinical studies have shown promising anticancer activity of Hsp90 inhibitors mainly in breast cancer, non small cell lung carcinoma (NSCLC), gastrointestinal stromal tumors (GIST) and various hematological malignancies. The universal involvement of Hsp90 in multiple oncogenic processes makes Hsp90 inhibitors ideal compounds to be explored as a single agent or in combination with other anticancer therapies.
Geldanamycin
Hsp90 inhibitor
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