Experimental Brain Research, Journal Year: 2024, Volume and Issue: 242(8), P. 1983 - 1998
Published: June 27, 2024
Language: Английский
Antioxidants, Journal Year: 2023, Volume and Issue: 12(4), P. 856 - 856
Published: April 1, 2023
It is well known that oxidative stress and lipid peroxidation (LPO) play a role in physiology pathology. The most studied LPO product with pleiotropic capabilities 4-hydroxynonenal (4-HNE). considered as an important mediator of cellular signaling processes second messenger reactive oxygen species. effects 4-HNE are mainly attributed to its adduction proteins. Whereas the Michael adducts thus formed preferred order potency cysteine > histidine lysine over Schiff base formation, it not which proteins targets for under what physiological or pathological conditions. In this review, we briefly discuss methods used identify 4-HNE–protein adducts, progress mass spectrometry deciphering specific protein targets, their biological relevance, focusing on adaptive response through modulation NRF2/KEAP1 pathway ferroptosis.
Language: Английский
Citations
51
MedComm, Journal Year: 2024, Volume and Issue: 5(2)
Published: Jan. 25, 2024
Abstract Heat shock protein 90 (Hsp90) is a predominant member among proteins (HSPs), playing central role in cellular protection and maintenance by aiding the folding, stabilization, modification of diverse substrates. It collaborates with various co‐chaperones to manage ATPase‐driven conformational changes its dimer during client processing. Hsp90 critical function, supporting proper operation numerous proteins, many which are linked diseases such as cancer, Alzheimer's, neurodegenerative conditions, infectious diseases. Recognizing significance these across diseases, there growing interest targeting for potential therapeutic strategies. This review described biological background HSPs structural characteristics HSP90. Additionally, it discusses regulatory heat factor‐1 (HSF‐1) modulating HSP90 sheds light on dynamic chaperone cycle Furthermore, specific contributions disease contexts, especially cancer. also summarizes inhibitors cancer treatment, offering thoughtful analysis their strengths limitations. These advancements research expand our understanding open up new avenues considering promising target intervention range
Language: Английский
Citations
30
Cell Stress and Chaperones, Journal Year: 2024, Volume and Issue: 29(4), P. 519 - 539
Published: June 13, 2024
The evolutionary conserved molecular chaperone HSP90 plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although, the functionality of is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis certain malignancies. While various strategies targeting heat shock proteins involved carcinogenesis have explored, only inhibition consistently and effectively resulted proteasomal degradation proteins. To date, total 22 inhibitors tested 186 clinical trials, as reported clinicaltrials.gov. Among these 60% completed, 10% are currently active, while 30% suspended, terminated, or withdrawn. used single agents combination other drugs for treatment types trials. Notably, improved outcomes observed when therapies, they synergistic antitumor effect. However, agents, shown limited activity due drug related toxicity therapy resistance. Recently, active trials conducted Japan evaluating TAS-116 (pimitespib) demonstrated promising results low monotherapy immune check point inhibitor nivolumab. Exploratory biomarker analyses performed target engagement that suggests potential identifying patient populations may respond favorably therapy. In review, we discuss advances made past five years regarding their implications anti-cancer therapeutics. Our focus lies efficacy, forecast, pharmacodynamic biomarkers, published Through comprehensive aim shed light progress therapeutic treatment.
Language: Английский
Citations
24
International Journal of Nanomedicine, Journal Year: 2023, Volume and Issue: Volume 18, P. 1433 - 1468
Published: March 1, 2023
Abstract: With the booming development of nanomedicine, mild photothermal therapy (mPTT, 42– 45°C) has exhibited promising potential in tumor therapy. Compared with traditional PTT (> 50°C), mPTT less side effects and better biological conducive to treatment, such as loosening dense structure tissues, enhancing blood perfusion, improving immunosuppressive microenvironment. However, a relatively low temperature cannot allow completely eradicate tumors, therefore, substantial efforts have been conducted optimize application This review extensively summarizes latest advances mPTT, including two sections: (1) taking leading role maximize its effect by blocking cell defense mechanisms, (2) regarding supporting assist other therapies achieve synergistic antitumor curative effect. Meanwhile, special characteristics imaging capabilities nanoplatforms applied various are discussed. At last, this paper puts forward bottlenecks challenges current research path possible solutions directions future proposed correspondingly. Keywords: nanotechnology, therapy,
Language: Английский
Citations
41
Theranostics, Journal Year: 2023, Volume and Issue: 13(7), P. 2281 - 2300
Published: Jan. 1, 2023
Heat Shock Factor 1 (HSF1) is a master regulator of heat shock responsive signaling. In addition to playing critical roles in cellular response, emerging evidence suggests that HSF1 also regulates non-heat transcriptional network handle metabolic, chemical, and genetic stress. The function transformation cancer development has been extensively studied recent years. Due important for coping with various stressful states, research on very active. New functions molecular mechanisms underlying these have continuously discovered, providing new targets novel treatment strategies. this article, we review the essential action cells, focusing more recently discovered their reflect advances biology. addition, emphasize regard inhibitors drug development.
Language: Английский
Citations
31
Cell Reports, Journal Year: 2024, Volume and Issue: 43(5), P. 114236 - 114236
Published: May 1, 2024
The tumor microenvironment (TME) presents cells with challenges such as variable pH, hypoxia, and free radicals, triggering stress responses that affect cancer progression. In this study, we examine the response landscape in four carcinomas—breast, pancreas, ovary, prostate—across five pathways: heat shock, oxidative stress, DNA damage, unfolded protein stress. Using a combination of experimental computational methods, create an atlas across various types carcinomas. We find vary within TME are especially active near cells. Focusing on non-immune stroma find, types, NRF2 distinctly activated immune-regulatory cancer-associated fibroblasts unique subset pericytes. Our study thus provides interactome cancer, offering ways to intersect survival pathways tumor, advance therapy.
Language: Английский
Citations
12
Theranostics, Journal Year: 2024, Volume and Issue: 14(6), P. 2442 - 2463
Published: Jan. 1, 2024
Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients.Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval use, primarily due issues such as induction heat shock response (HSR), off-target effects, and unfavorable toxicity profiles.We sought examine effects HVH-2930, novel C-terminal inhibitor, overcoming resistance.Methods: The effect HVH-2930 on trastuzumab-sensitive -resistant cell lines vitro was evaluated terms viability, expression client proteins, impact stem cells.An vivo model with trastuzumab-resistant JIMT-1 cells used efficacy HVH-2930.Results: rationally designed fit into ATP-binding pocket interface cavity hHSP90 homodimer domain HSP90, stabilizing its open conformation hindering ATP binding.HVH-2930 induces apoptosis without inducing HSR but by specifically suppressing HER2 signaling pathway.This occurs downregulation HER2/p95HER2 disruption family member heterodimerization.Attenuation (CSC)-like properties associated stemness factors ALDH1, CD44, Nanog Oct4.Furthermore, administration inhibited angiogenesis tumor growth xenograft mice.A synergistic observed when combining paclitaxel xenografts.Conclusion: Our findings highlight potent resistance cancer.Further investigation is warranted fully establish therapeutic potential.
Language: Английский
Citations
9
Chemical Research in Toxicology, Journal Year: 2022, Volume and Issue: 35(10), P. 1690 - 1700
Published: Aug. 10, 2022
Cellular homeostasis is continuously challenged by damage from reactive oxygen species (ROS) and numerous electrophiles. Human cells contain various protective systems that are upregulated in response to protein electrophilic or oxidative stress. In addition the NRF2-mediated antioxidant response, ROS electrophiles also activate HSF1 HIF1 control heat shock hypoxia respectively. Here, we review chemical biological mechanisms of activation these three transcription factors ROS/reactive toxicants roles their gene expression programs protection. We discuss how NRF2, HSF1, responses establish multilayered cellular defenses consisting largely nonoverlapping programs, which mitigates limitations each response. Some innate immunity links stress help eliminate damaged cells, whereas others suppress deleterious inflammation normal tissues but inhibit immunosurveillance cancer tumors.
Language: Английский
Citations
32
Cancers, Journal Year: 2023, Volume and Issue: 15(3), P. 984 - 984
Published: Feb. 3, 2023
Heat-shock proteins (HSPs) are powerful chaperones that provide support for cellular functions under stress conditions but also the homeostasis of basic machinery. All cancer cells strongly rely on HSPs, as they must continuously adapt to internal microenvironmental stresses survive. In solid tumors, HSPs have been described helping correct folding misfolded proteins, sustain oncogenic pathways, and prevent apoptosis. Leukemias lymphomas overexpress which frequently associated with resistance therapy. therefore proposed new therapeutic targets. Given specific biology hematological malignancies, it is essential revise their role in this field, providing a more adaptable comprehensive picture would help design future clinical trials. To end, review will describe different pathways regulated by HSP27, HSP70, HSP90, and, not least, HSP110 leukemias lymphomas.
Language: Английский
Citations
21
Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(8), P. 5907 - 5936
Published: April 5, 2023
CCT251236 1, a potent chemical probe, was previously developed from cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, factor that supports malignancy. Owing its activity against models refractory human ovarian cancer, 1 progressed into lead optimization. The reduction P-glycoprotein efflux became focus early compound optimization; central ring halogen substitution demonstrated matched molecular pair analysis be an effective strategy mitigate this liability. Further multiparameter optimization led the design clinical candidate, CCT361814/NXP800 22, and orally bioavailable fluorobisamide, which caused tumor regression in adenocarcinoma xenograft model with on-pathway biomarker modulation clean vitro safety profile. Following favorable dose prediction human, 22 has now phase trial as potential future treatment for cancer other malignancies.
Language: Английский
Citations
17