Detrimental effects of geldanamycin on adults and larvae of Trichinella spiralis

SummaryTrichinellosis is a zoonotic disease affecting mainly the temperate regions. The treatment is a challenge for the physician, and the available therapy is far from ideal. Therefore, this work aimed to evaluate the effect of heat shock protein 90 inhibitor, geldanamycin, on the adult worms and larvae of Trichinella spiralis. This research comprised an in vivo study in which T. spiralis-infected mice were treated by two different doses of geldanamycin, thereafter larval count and pathological changes were determined in the muscles. Meanwhile, the in vitro study investigated the effect of two different concentrations of geldanamycin on adult worms and larvae of T. spiralis via transmission electron microscopy. The in vivo study showed significant reduction of muscle larval counts under the effect of geldanamycin. Moreover, characteristic changes were noted as regards the parasite and the inflammatory response. The in vitro study revealed degenerative changes in the body wall of larvae and adults of T. spiralis under the influence of geldanamycin. In conclusion, heat shock protein 90 inhibitor, geldanamycin, seems to have detrimental effects on the adults and larvae of T. spiralis. It, or one of its derivatives, could be an adjuvant to anthelmintic therapy of trichinellosis, but more studies are warranted to establish its usefulness.

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Faculty Opinions recommendation of Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1082926.535884 ◽

2007 ◽

Author(s):

Homer Pearce

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Molecular Chaperone ◽

Heat Shock Protein 90

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Faculty Opinions recommendation of A pivotal role for heat shock protein 90 in Ewing sarcoma resistance to anti-insulin-like growth factor 1 receptor treatment: in vitro and in vivo study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1120094.576229 ◽

2008 ◽

Author(s):

Richard Riedel

Keyword(s):

Growth Factor ◽

Heat Shock ◽

Heat Shock Protein ◽

Ewing Sarcoma ◽

Heat Shock Protein 90 ◽

Pivotal Role ◽

In Vivo Study ◽

Insulin Like Growth Factor

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In vivo-in vitro correlation of antitumor activity of heat shock protein 90 (HSP90) inhibitors with a pharmacokinetics/pharmacodynamics analysis using NCI-N87 xenograft mice

Xenobiotica ◽

10.1080/00498254.2021.1942588 ◽

2021 ◽

pp. 1-30

Author(s):

Noriaki Ohminato ◽

Miho Nagayasu ◽

Kazuhisa Ozeki ◽

Ryoichi Saitoh ◽

Naomi Ono ◽

...

Keyword(s):

Heat Shock ◽

Antitumor Activity ◽

Heat Shock Protein ◽

Heat Shock Protein 90 ◽

Hsp90 Inhibitors ◽

Xenograft Mice

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A Brain Penetrating Heat-Shock Protein 90 Inhibitor NXD30001 Inhibits Glioblastoma as a Monotherapy or in Combination With Radiation

Neurosurgery ◽

10.1093/neuros/nyz310_218 ◽

2019 ◽

Vol 66 (Supplement_1) ◽

Cited By ~ 1

Author(s):

Hao Chen ◽

Jialiang Wang ◽

Hengli Tian

Keyword(s):

Stem Cells ◽

Heat Shock ◽

Heat Shock Protein ◽

Median Survival ◽

Therapeutic Potential ◽

Heat Shock Protein 90 ◽

Tumor Bearing ◽

Client Proteins

Abstract INTRODUCTION It has been increasingly recognized that glioblastoma multiforme (GBM) is a highly heterogeneous disease, which is initiated and sustained by molecular alterations in an array of signal transduction pathways. Heat-shock protein 90 (Hsp90) is a molecular chaperone to be critically implicated in folding and activation of a diverse group of client proteins, many of which are key regulators of important glioblastoma biology. METHODS To determine the therapeutic potential of targeting Hsp90 in glioblastoma, we assessed the anti-neoplastic efficacy of NXD30001, a brain-penetrating Hsp90 inhibitor as a monotherapy or in combination with radiation, both in Vitro and in Vivo. RESULTS Our results demonstrated that NXD30001 potently inhibited neurosphere formation, growth and survival of CD133 + glioblastoma stem cells (GSCs) with the half maximal inhibitory concentrations (IC50) at low nanomolar concentrations. At suboptimal concentrations, inhibition of Hsp90 did not exert cytotoxic activity but rather increased radiosensitivity in GSCs. CD133- GBM cells were less sensitive and not radiosensitized by NXD30001. In lines with its cytotoxic and radiosensitizing effects, NXD30001 dose-dependently decreased phosphorylation protein levels of multiple Hsp90 client proteins, including those playing key roles in GSCs, such as EGFR, Akt, c-Myc, and Notch1. In addition, combining NXD30001 with radiation could impair DNA damage response and ER stress response to induce apoptosis of GSCs. Treatment of orthotopic glioblastoma tumors with NXD30001 extended median survival of tumor-bearing mice by approximately 20% (treated 37 days vs vehicle 31 d, P = .0026). Radiation alone increased median survival of tumor-bearing mice from 31 to 38 d, combination with NXD30001 further extended survival to 43 d (P = .0089). CONCLUSION Our results suggest that GBM stem cells (CD133+) are more sensitive to NXD30001 than non-stem GBM cells (CD133-). Furthermore, combination NXD30001 with radiation significantly inhibits GBM progression than use it as a monotherapy by targeting GSCs.

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