HSP90 and HSP70: Implication in Inflammation Processes and Therapeutic Approaches for Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPN) are clonal stem cell disorders that lead to the excessive production of one or more blood cell lineages. It has been reported that, in most MPN, inflammatory cytokines are frequently increased, indicating that inflammation plays a crucial role in these disorders. Heat shock proteins (HSP) are induced in response to many stressful conditions from heat shock to hypoxia and inflammation. Besides their chaperone and cytoprotective functions, HSPs are key players during inflammation, hence the term “chaperokine.” Through their chaperone activity, HSP90, a stabilizer of many oncogenes (e.g., JAK2), and HSP70, a powerful antiapoptotic chaperone, tightly regulate Nuclear Factor-kappa B signalling, a critical pathway in mediating inflammatory responses. In light of this potential, several HSP90 inhibitors have been generated as anticancer agents able to degrade oncogenes. As it turns out, however, these drugs are also potent inhibitors of the inflammatory response in various diseases. Given the chaperone potential of HSP70 and the fact that HSP90 inhibitors induce HSP70, interest in HSP70 inhibitors is also increasing. Here, we focus on the implication of HSP90 and HSP70 in inflammatory responses and on the emergence of new therapeutic approaches in MPN based on HSP inhibitors.

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Recent Developments in Anticancer Agents Targeting Heat Shock Proteins

Topics in Anti-Cancer Research ◽

10.2174/9781681083339116050008 ◽

2016 ◽

pp. 205-224

Author(s):

Aykut Özgür ◽

Banu Bayram ◽

Lütfi Tutar ◽

Yusuf Tutar

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Anticancer Agents ◽

Recent Developments ◽

Shock Proteins

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Poly(ADP-Ribose) Polymerase-1 Inhibitors Drug Discovery, Design, and Development as Anticancer Agents from Past to Present: A Mini-Review

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210929144045 ◽

2021 ◽

Vol 21 ◽

Author(s):

Arwa AlGhamdi ◽

Hanine AlMubayedh

Keyword(s):

Anticancer Agents ◽

Parp Inhibitor ◽

Advanced Ovarian Cancer ◽

Therapeutic Approaches ◽

Repair Mechanism ◽

Design And Development ◽

Cancer Treatments ◽

New Therapeutic Approaches ◽

Life Threatening ◽

Cancerous Cells

Abstract: Cancer treatments are known for their life-threatening toxicities attributed to their low selectivity; hence, new therapeutic approaches are being developed as alternatives. Among those approaches is the DNA repair mechanism, where its inhibition results selectively in the death of cancerous cells. Poly(ADP-Ribose) Polymerase (PARP) is one of the enzymes involved in the repair of damaged DNA. The inhibition of PARP shows to be a promising approach for effective targeted treatment of cancer, especially in tumours with pre-existing Homologous-Repair (HR) defects (i.e., BRCA). Nicotinamide, which is one of the PARP catalytic products, was the first identified PARP inhibitor (PARPi). The first FDA-approved PARPi was Olaparib in 2014 for the treatment of BRCA mutated advanced ovarian cancer. Several clinical trials have been conducted to further improve PARPi. However, there are some concerns related to drug resistance, PARPi sensitive-tumour identification, and toxic accumulation of PARPi. This report will review the uses of PARPi, drug design and development of PARPi from past to present, current issues, and prospective plans.

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Heat shock proteins in health and disease: therapeutic targets or therapeutic agents?

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399401003556 ◽

2001 ◽

Vol 3 (23) ◽

pp. 1-21 ◽

Cited By ~ 49

Author(s):

A. Graham Pockley

Keyword(s):

Heat Shock ◽

Autoimmune Disease ◽

Heat Shock Proteins ◽

Inflammatory Responses ◽

Therapeutic Targets ◽

Disease Process ◽

Therapeutic Agents ◽

Immune Reactivity ◽

Shock Proteins ◽

Extracellular Environment

For many years, heat shock or stress proteins have been regarded as intracellular molecules that have a range of housekeeping and cytoprotective functions, only being released into the extracellular environment in pathological situations such as necrotic cell death. However, evidence is now accumulating to indicate that, under certain circumstances, these proteins can be released from cells in the absence of cellular necrosis, and that extracellular heat shock proteins have a range of immunoregulatory activities. The capacity of heat shock proteins to induce pro-inflammatory responses, together with the phylogenetic similarity between prokaryotic and eukaryotic heat shock proteins, has led to the proposition that these proteins provide a link between infection and autoimmune disease. Indeed, both elevated levels of antibodies to heat shock proteins and an enhanced immune reactivity to heat shock proteins have been noted in a variety of pathogenic disease states. However, further evaluation of heat shock protein reactivity in autoimmune disease and after transplantation has shown that, rather than promoting disease, reactivity to self-heat shock proteins can downregulate the disease process. It might be that self-reactivity to heat shock proteins is a physiological response that regulates the development and progression of pro-inflammatory immunity to these ubiquitously expressed molecules. The evolving evidence that heat shock proteins are present in the extracellular environment, that reactivity to heat shock proteins does not necessarily reflect adverse, pro-inflammatory responses and that the promotion of reactivity to self-heat shock proteins can downregulate pathogenic processes all suggest a potential role for heat shock proteins as therapeutic agents, rather than as therapeutic targets.

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Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms

Cancers ◽

10.3390/cancers12092592 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2592

Author(s):

Steven De Almeida ◽

Mathilde Regimbeau ◽

Gaëtan Jego ◽

Carmen Garrido ◽

François Girodon ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Myeloproliferative Neoplasms ◽

Therapeutic Targets ◽

Janus Kinase ◽

Driver Mutations ◽

Hematopoietic Stem ◽

Stat3 Phosphorylation ◽

Stat Signaling ◽

Shock Proteins

Myeloproliferative neoplasms (MPN) are a group of clonal disorders that affect hematopoietic stem/progenitor cells. These disorders are often caused by oncogenic driver mutations associated with persistent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. While JAK inhibitors, such as ruxolitinib, reduce MPN-related symptoms in myelofibrosis, they do not influence the underlying cause of the disease and are not curative. Due to these limitations, there is a need for alternative therapeutic strategies and targets. Heat shock proteins (HSPs) are cytoprotective stress-response chaperones involved in protein homeostasis and in many critical pathways, including inflammation. Over the last decade, several research teams have unraveled the mechanistic connection between STAT signaling and several HSPs, showing that HSPs are potential therapeutic targets for MPN. These HSPs include HSP70, HSP90 (chaperoning JAK2) and both HSP110 and HSP27, which are key factors modulating STAT3 phosphorylation status. Like the HSPs, the PD-1/PD-L1 signaling pathway has been widely studied in cancer, but the importance of PD-L1-mediated immune escape in MPN was only recently reported. In this review, we summarize the role of HSPs and PD-1/PD-L1 signaling, the modalities of their experimental blockade, and the effect in MPN. Finally, we discuss the potential of these emerging targeted approaches in MPN therapy.

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Heat Shock Proteins as Immunomodulants

Molecules ◽

10.3390/molecules23112846 ◽

2018 ◽

Vol 23 (11) ◽

pp. 2846 ◽

Cited By ~ 53

Author(s):

Tawanda Zininga ◽

Lebogang Ramatsui ◽

Addmore Shonhai

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Immune Cells ◽

Metabolic Pathways ◽

Immune Modulation ◽

Inflammatory Responses ◽

Main Role ◽

Enhanced Secretion ◽

Response To Stress ◽

Shock Proteins

Heat shock proteins (Hsps) are conserved molecules whose main role is to facilitate folding of other proteins. Most Hsps are generally stress-inducible as they play a particularly important cytoprotective role in cells exposed to stressful conditions. Initially, Hsps were generally thought to occur intracellulary. However, recent work has shown that some Hsps are secreted to the cell exterior particularly in response to stress. For this reason, they are generally regarded as danger signaling biomarkers. In this way, they prompt the immune system to react to prevailing adverse cellular conditions. For example, their enhanced secretion by cancer cells facilitate targeting of these cells by natural killer cells. Notably, Hsps are implicated in both pro-inflammatory and anti-inflammatory responses. Their effects on immune cells depends on a number of aspects such as concentration of the respective Hsp species. In addition, various Hsp species exert unique effects on immune cells. Because of their conservation, Hsps are implicated in auto-immune diseases. Here we discuss the various metabolic pathways in which various Hsps manifest immune modulation. In addition, we discuss possible experimental variations that may account for contradictory reports on the immunomodulatory function of some Hsps.

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Ins and Outs of Heat Shock Proteins in Colorectal Carcinoma: Its Role in Carcinogenesis and Therapeutic Perspectives

Cells ◽

10.3390/cells10112862 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2862

Author(s):

Batoul Abi Zamer ◽

Waseem El-Huneidi ◽

Mohamed Ahmed Eladl ◽

Jibran Sualeh Muhammad

Keyword(s):

Heat Shock ◽

Colorectal Carcinoma ◽

Heat Shock Proteins ◽

Cancer Cells ◽

Anticancer Agents ◽

Inflammatory Conditions ◽

Metabolic Activities ◽

Novel Therapeutic Strategies ◽

Shock Proteins ◽

Functional Mechanisms

Cancer cells can reprogram their metabolic activities and undergo uncontrolled proliferation by utilizing the power of heat shock proteins (HSPs). HSPs are highly conserved chaperones that facilitate the folding of intracellular proteins under stress. Constitutively, HSPs are expressed at low levels, but their expression upregulates in response to a wide variety of insults, including anticancer drugs, allowing cancer cells to develop chemoresistance. In recent years, several researchers have reported that HSPs could be an important therapeutic target in difficult-to-treat cancers such as colorectal carcinoma (CRC). Worldwide, CRC is the second most common type of cancer and the second leading cause of cancer-related deaths. The molecular complexity of CRC and the coexisting inflammatory conditions present a significant obstacle to developing effective treatment. Recently, considerable progress has been made in enhancing our understanding of the role of HSPs in CRC pathogenesis. Moreover, novel therapeutic strategies targeting HSPs, either alone or in combination with other anticancer agents, have been reported. Herein, we present an overview of the functional mechanisms and the diagnostic and prognostic potential of HSPs in CRC. We also discuss emerging anti-CRC strategies based on targeting HSPs.

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