RP101 (brivudine) binds to heat shock protein HSP27 (HSPB1) and enhances survival in animals and pancreatic cancer patients

Heinrich, Jörg‐Christian; Tuukkanen, Anne; Schroeder, Michael; Fahrig, Torsten; Fahrig, Rudolf

doi:10.1007/s00432-011-1005-1

Cited by 91 publications

(102 citation statements)

References 44 publications

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“…In addition to depleting HSPB1 by antisense or RNA interference (RNAi) strategy [27,32,33], disturbing its structural organization and subsequently its interaction with particular client polypeptides appears as another approach that can alter HSPB1 ability to promote tumour growth. For example, the drug brivudine improves the efficiency of human pancreatic cancer chemotherapy by impairing the ability of HSPB1 to block apoptosis through the recognition of pathological protein substrates [34]. We have been interested in the peptide aptamers (PAs) technology to target HSPB1 structure/function.…”

Section: Introductionmentioning

confidence: 99%

Peptide aptamers: tools to negatively or positively modulate HSPB1(27) function

Gibert

Simon

Dimitrova

et al. 2013

Phil. Trans. R. Soc. B

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Human HSP27 (HSPB1) is a molecular chaperone sensor which, through dynamic changes in its phosphorylation and oligomerization, allows cells to adapt to changes in their physiology and/or mount a protective response to injuries. In pathological conditions, the high level of HSPB1 expression can either be beneficial, such as in diseases characterized by cellular degenerations, or be malignant in cancer cells where it promotes tumourigenesis, metastasis and anti-cancer drug resistance. Structural changes allow HSPB1 to interact with specific client protein partners in order to modulate their folding/activity and/or half-life. Therefore, the search is open for therapeutic compounds aimed at either down- or upregulating HSPB1 activity. In this respect, we have previously described two peptide aptamers (PA11 and PA50) that specifically interact with HSPB1 small oligomers and decrease its anti-apoptotic and tumourigenic activities. A novel analysis of the different HSPB1-interacting aptamers that were isolated earlier revealed that one aptamer (PA23) has the intriguing ability to stimulate the protective activity of HSPB1. We show here that this aptamer abolishes the dominant negative effect induced by the R120G mutant of αB-crystallin (HSPB5) by disrupting its interaction with HSPB1. Hence, developing structure-based interfering strategies could lead to the discovery of HSPB1-based therapeutic drugs.

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Section: Introductionmentioning

confidence: 99%

Peptide aptamers: tools to negatively or positively modulate HSPB1(27) function

Gibert

Simon

Dimitrova

et al. 2013

Phil. Trans. R. Soc. B

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“…On the other hand, if its expression being ceased in cancers, that can regress the tumor growth as well (33). A study was conducted on Hspb1 to RP101 (Brivudine) showed an improved effi cacy in chemotherapy of human pancreatic and rat cancers (34). In this study, both lymphoma samples (Lymph-1, Lymph-2) revealed altered expression of Hspb1 (Fig.…”

Section: Discussionmentioning

confidence: 67%

Expression Profi ling of Hspb1 and Tp53 Genes through RT-qPCR in Different Cancer Types of Canis familiaris

Saif

Awan

Tayyab

et al. 2017

Iran. J. Biotechnol.

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Background: Diagnostic molecular marker studies are in vogue to have insight of most prevalent animal diseases including cancer. Objectives: Gene expression profi ling of pro and anti-apoptotic genes was conducted in dog Lymphoma, CTVT, SCC, granuloma, perianal adenocarcinoma and mammary tumors. Materials and Methods: Cancerous tissues of 21 aff ected animals were obtained. Total RNA was extracted followed by cDNA synthesis. Comparative Ct method via Taqman assay (RT-qPCR) was used to quantify corresponding mRNA molecules, Tp53 and Hspb1, as normalized by GAPDH as the reference gene . Results: Hspb1 showed ectopic expression in lymphoma, CTVT and mammary tumors; its down-regulation was observed in granuloma and oral SCC with fold diff erence (FD) of ±35. Similarly, Tp53 as the tumor suppressor gene with proapoptotic properties, showed up-regulation in all tumor types, notably 80% of mammary tumors and 60% of CTVT. The FD values were 33.31 and 2.27, respectively. Conclusion: Altered transcriptomic response of Hspb1 and Tp53 was observed in all cancer types of Canis familiaris. The resulting profi le depicts the involvement of the genes in cancer pathways. Thus, the data might be helpful for diagnosis, prognosis, identifi cation and classifi cation of these widespread neoplasms in this species.

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“…Hsp27 expression inhibitors include: (a) Bromovinyl-deoxyuridine (RP101, Fig. 5) [51], (b) 5-(5-ethyl-2-hydroxy-4-methoxyphenyl)-4-(4-methoxyphenyl) isoxazole (KRIBB, Fig. 5) [52] and (c) quercetin (Fig.…”

Section: Small-molecule Hsp27 Protein Regulatorsmentioning

confidence: 99%

Heat Shock Protein 27: Structure, Function, Cellular Role and Inhibitors

Mehmood

McAlpine

2015

Topics in Medicinal Chemistry

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Hsp27 is an important heat shock protein found in all organisms from prokaryotes to mammals. It is a structurally conserved ATP-independent protein, present in both normal and abnormal tissues. Its expression and induction occur under stressed conditions. The self-association to form oligomers and subsequent equilibrium between oligomer and dimer play critical roles in regulating Hsp27's function. Site-specific phosphorylation of Hsp27 regulates this equilibrium, controlling the activity of Hsp27. Hsp27's molecular chaperone activity includes interacting with a large number of proteins and regulating their folding states. Significant levels of Hsp27 expression have been observed in many diseases, including cancer, neuronal diseases and cardiac diseases. Herein we describe the current understanding of Hsp27's structure, function, cellular role and inhibitors.

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RP101 (brivudine) binds to heat shock protein HSP27 (HSPB1) and enhances survival in animals and pancreatic cancer patients

Abstract: The development of RP101 as a cancer drug represents a truly novel approach for prevention of chemoresistance and enhancement of chemosensitivity.

Cited by 91 publications

References 44 publications

Peptide aptamers: tools to negatively or positively modulate HSPB1(27) function

Peptide aptamers: tools to negatively or positively modulate HSPB1(27) function

Expression Profi ling of Hspb1 and Tp53 Genes through RT-qPCR in Different Cancer Types of Canis familiaris

Heat Shock Protein 27: Structure, Function, Cellular Role and Inhibitors

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