Heat shock proteins and cancer: The FoxM1 connection

Alimardan, Zahra; Abbasi, Maryam; Hasanzadeh, Farshid; Aghaei, Mahmud; Khodarahmi, Ghadamali; Kashfi, Khosrow

doi:10.1016/j.bcp.2023.115505

Cited by 11 publications

(6 citation statements)

References 146 publications

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“…Notably, as HSP70 inhibition is known to be advantageous for the development of anti-cancer agents [ 40 , 41 ], the identification of dual inhibitors (against HSP70 and SIRT2) may represent a promising strategy for contrasting tumors.…”

Section: Discussionmentioning

confidence: 99%

Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays

Abbotto,

Casini,

Piacente

et al. 2023

Pharmaceuticals

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Recently, the development of sirtuin small molecule inhibitors (SIRTIs) has been gaining attention for the treatment of different cancer types, but also to contrast neurodegenerative disease, diabetes, and autoimmune syndromes. In the search for SIRT2 modulators, the availability of several X-crystallographic data regarding SIRT2−ligand complexes has allowed for setting up a structure-based study, which is herein presented. A set of 116 SIRT2 inhibitors featuring different chemical structures has been collected from the literature and used for molecular docking studies involving 4RMG and 5MAT PDB codes. The information found highlights key contacts with the SIRT2 binding pocket such as Van der Waals and π–π stacking with Tyr104, Phe119, Phe234, and Phe235 in order to achieve high inhibitory ability values. Following the preliminary virtual screening studies, a small in-house library of compounds (1a–7a), previously investigated as putative HSP70 inhibitors, was described to guide the search for dual-acting HSP70/SIRT2 inhibitors. Biological and enzymatic assays validated the whole procedure. Compounds 2a and 7a were found to be the most promising derivatives herein proposed.

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Section: Discussionmentioning

confidence: 99%

Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays

Abbotto,

Casini,

Piacente

et al. 2023

Pharmaceuticals

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“…Typically, these and other chaperones are cytoprotective, but if abnormal in structure–function, quantity, and/or location, they can cause diseases, known as chaperonopathies [ 9 , 10 ]. Chaperones can favor carcinogenesis through various mechanisms, as shown by many experimental and clinical data [ 11 , 12 , 13 ]. For example, high tissue levels of certain Hsps are often associated with cancer progression and invasiveness, suggesting that these proteins favor, in some types of tumors, the tendency to invade surrounding tissues and to spread to distant organs [ 6 , 7 , 14 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

Immunomorphological Patterns of Chaperone System Components in Rare Thyroid Tumors with Promise as Biomarkers for Differential Diagnosis and Providing Clues on Molecular Mechanisms of Carcinogenesis

Paladino

Santonocito

Graceffa

et al. 2023

Cancers

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Hurthle cell (HC), anaplastic (AC), and medullary (MC) carcinomas are low frequency thyroid tumors that pose several challenges for physicians and pathologists due to the scarcity of cases, information, and histopathological images, especially in the many areas around the world in which sophisticated molecular and genetic diagnostic facilities are unavailable. It is, therefore, cogent to provide tools for microscopists to achieve accurate diagnosis, such as histopathological images with reliable biomarkers, which can help them to reach a differential diagnosis. We are investigating whether components of the chaperone system (CS), such as the molecular chaperones, can be considered dependable biomarkers, whose levels and distribution inside and outside cells in the tumor tissue could present a distinctive histopathological pattern for each tumor type. Here, we report data on the chaperones Hsp27, Hsp60, and Hsp90. They presented quantitative levels and distribution patterns that were different for each tumor and differed from those of a benign thyroid pathology, goiter (BG). Therefore, the reported methodology can be beneficial when the microscopist must differentiate between HC, AC, MC, and BG.

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“…Heat shock proteins (HSPs; e.g., HSP70 and HSP90) are key tumor defense proteins in PTT. , When stimulated by high temperatures, HSPs are rapidly upregulated to exert central antiapoptotic and cytoprotective effects as chaperones and restore denatured proteins, thereby preventing cell death . Specific HSP inhibitors − or small interfering RNA (siRNA) − have been introduced into nanoscale drug-delivery systems to improve the thermal sensitivity of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Self-Delivery Nanomedicines Reverse Thermal Resistance to Enhance Tumor Mild-Temperature Photothermal Therapy

Lai,

Shi,

Xie

et al. 2024

Mol. Pharmaceutics

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Tumoral thermal defense mechanisms considerably attenuate the therapeutic outcomes of mild-temperature photothermal therapy (PTT). Thus, developing a simple, efficient, and universal therapeutic strategy to sensitize mild-temperature PTT is desirable. Herein, we report self-delivery nanomedicines ACy NPs comprising a near-infrared (NIR) photothermal agent (Cypate), mitochondrial oxidative phosphorylation inhibitor (ATO), and distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE−PEG 2000 ), which have a high drug-loading efficiency that can reverse tumoral thermal resistance, thereby increasing mildtemperature PTT efficacy. ACy NPs achieved targeted tumor accumulation and performed NIR fluorescence imaging capability in vivo to guide tumor PTT for optimized therapeutic outcomes. The released ATO reduced intracellular ATP levels to downregulate multiple heat shock proteins (including HSP70 and HSP90) before PTT, which reversed the thermal resistance of tumor cells, contributing to the excellent results of mild-temperature PTT in vitro and in vivo. Therefore, this study provides a simple, biosafe, advanced, and universal heat shock protein-blocking strategy for tumor PTT.

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Heat shock proteins and cancer: The FoxM1 connection

Cited by 11 publications

References 146 publications

Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays

Novel Thiazole-Based SIRT2 Inhibitors Discovered via Molecular Modelling Studies and Enzymatic Assays

Immunomorphological Patterns of Chaperone System Components in Rare Thyroid Tumors with Promise as Biomarkers for Differential Diagnosis and Providing Clues on Molecular Mechanisms of Carcinogenesis

Self-Delivery Nanomedicines Reverse Thermal Resistance to Enhance Tumor Mild-Temperature Photothermal Therapy

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