Hsp70 chaperone-based gel composition as a novel immunotherapeutic anti-tumor tool

Abkin, Sergey V.; Pankratova, Katerina M.; Комарова, Е. В.; Guzhova, Irina V.; Margulis, Boris A.

doi:10.1007/s12192-012-0391-x

Cited by 25 publications

(29 citation statements)

References 17 publications

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“…For examples, HSP70 in a hydrogel composition was applied on the skin surface on top of B16 mouse melanoma. In this case, significant inhibition of tumor growth and elevation of the survival rate was reported [153].…”

Section: P C W Fung R K C Kong Journal Of Cancer Therapymentioning

confidence: 66%

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Fung¹,

Kong²

2017

JCT

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Heat shock proteins (HSPs) serve to correct proteins' conformation, send the damaged proteins for degradation (quality control function). Heat shock factors (HSFs) are their transcription factors. The protein complexes mTOR1 and 2 (with the same core mTOR), the phosphoinositide-dependent protein kinase-1 (PDK1), the seine/threonine-specific protein kinase (Akt), HSF1, plus their associated proteins form a network participating in protein synthesis, bio-energy generation, signaling for apoptosis with the help of HSPs. A cancer cell synthesizes proteins at fast rate and needs more HSPs to work on quality control. Shutting down this network would lead to cell death. Thus inhibitors of mTOR (mTORI) and inhibitors of HSPs (HSPI) could drive cancer cell to apoptosis-a "passive approach". On the other hand, HSPs form complexes with polypeptides characteristic of the cancer cells; on excretion from the cell, they becomes antigens for the immunity cells, eventually leading to maturation of the cytotoxic T cells, forming the basic principle of preparing cancer-specific, person-specific vaccine. Recent finding shows that HSP70 can penetrate cancer cell and expel its analog to extracellular region, giving the hope to prepare a non-person-specific vaccine covering a variety of cancers. Activation of anti-cancer immunity is the "active approach". On the other hand, mild hyperthermia, with increase of intracellular HSPs, has been found to activate the immunity response, and demonstrate anti-cancer effects. There are certain "mysteries" behind the mechanisms of the active and passive approaches. We analyze the mechanisms involved and provide explanations to some mysteries. We also suggest future research to improve our understanding of these two approaches, in which HSPs play many roles.

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Section: P C W Fung R K C Kong Journal Of Cancer Therapymentioning

confidence: 66%

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Fung¹,

Kong²

2017

JCT

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“…Thus, exogenous Hsp70 introduced intratumorally could penetrate tumor cells and induce translocation of intracellular Hsp70 toward the plasma membrane, enhancing immunorecognition of the tumor cells. Uptake of Hsp70 by tumor cells has been reported previously in models of C6 glioblastoma and B16 melanoma 14,15,43. The preferential accumulation of Hsp70 protein in C6 glioblastoma cells could be explained by CD40 receptor-mediated uptake of chaperone 44.…”

Section: Discussionmentioning

confidence: 60%

Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children

Shevtsov

Kim²,

Samochernych³

et al. 2014

OTT

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Intratumoral injections of recombinant heat shock protein (Hsp)70 were explored for feasibility in patients with brain tumors. Patients aged 4.5–14 years with untreated newly diagnosed tumors (n=12) were enrolled. After tumor resection, five injections of recombinant Hsp70 (total 2.5 mg) were administered into the resection cavity through a catheter. Before administration of Hsp70 and after the last injection, specific immune responses to the autologous tumor lysate were evaluated using the delayed-type hypersensitivity test. Further, peripheral blood was monitored to identify possible changes in lymphocyte subpopulations, cytokine levels, and the cytolytic activity of natural killer cells. The follow-up period in this trial was 12 months. Intratumoral injections of Hsp70 were well tolerated by patients. One patient had a complete clinical response documented by radiologic findings and one patient had a partial response. A positive delayed-type hypersensitivity test was observed in three patients. In peripheral blood, there was a shift from cytokines provided by Th2 cells toward cytokines of a Th1-cell-mediated response. These data corresponded to changes in lymphocyte subpopulations. Immunosuppressive T-regulatory cell levels were also reduced after injection of Hsp70, as well as production of interleukin-10. The cytolytic activity of natural killer cells was unchanged. The present study demonstrates the feasibility of intratumoral delivery of recombinant Hsp70 in patients with cancer. Further randomized clinical trials are recommended to assess the optimum dose of the chaperone, the treatment schedule, and clinical efficacy.

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“…It has previously been reported by Luginbuehl et al that cellular response rates for an encapsulated protein (insulin-like growth factor I [IGF-I]) were noticeably increased due to the constant release of high concentrations of the protein from alginate capsules into the extracellular milieu 35. The importance of long-term delivery in regard to the therapeutic activity of Hsp70 has been demonstrated previously by our group in immunotherapy studies related to B16 mouse melanoma and C6 glioblastoma 36,37. Presumably, maintaining a high level of Hsp70 in the body provides a constant supply of neuroprotectors to the intracellular chaperone machinery as well as a continuous anti-inflammatory influence in the microenvironment within the ischemic zone.…”

Section: Discussionmentioning

confidence: 85%

Neurotherapeutic activity of the recombinant heat shock protein Hsp70 in a model of focal cerebral ischemia in rats

Shevtsov¹,

Nikolaev²,

Yakovleva³

et al. 2014

DDDT

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Recombinant 70 kDa heat shock protein (Hsp70) is an antiapoptotic protein that has a cell protective activity in stress stimuli and thus could be a useful therapeutic agent in the management of patients with acute ischemic stroke. The neuroprotective and neurotherapeutic activity of recombinant Hsp70 was explored in a model of experimental stroke in rats. Ischemia was produced by the occlusion of the middle cerebral artery for 45 minutes. To assess its neuroprotective capacity, Hsp70, at various concentrations, was intravenously injected 20 minutes prior to ischemia. Forty-eight hours after ischemia, rats were sacrificed and brain tissue sections were stained with 2% triphenyl tetrazolium chloride. Preliminary treatment with Hsp70 significantly reduced the ischemic zone (optimal response at 2.5 mg/kg). To assess Hsp70’s neurotherapeutic activity, we intravenously administered Hsp70 via the tail vein 2 hours after reperfusion (2 hours and 45 minutes after ischemia). Rats were then kept alive for 72 hours. The ischemic region was analyzed using a high-field 11 T MRI scanner. Administration of the Hsp70 decreased the infarction zone in a dose-dependent manner with an optimal (threefold) therapeutic response at 5 mg/kg. Long-term treatment of the ischemic rats with Hsp70 formulated in alginate granules with retarded release of protein further reduced the infarct volume in the brain as well as apoptotic area (annexin V staining). Due to its high neurotherapeutic potential, prolonged delivery of Hsp70 could be useful in the management of acute ischemic stroke.

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Hsp70 chaperone-based gel composition as a novel immunotherapeutic anti-tumor tool

Cited by 25 publications

References 17 publications

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children

Neurotherapeutic activity of the recombinant heat shock protein Hsp70 in a model of focal cerebral ischemia in rats

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