Profound activity of the anti-cancer drug bortezomib against Echinococcus multilocularis metacestodes identifies the proteasome as a novel drug target for cestodes.

Lundström-Stadelmann, Britta; Aeschbacher, Denise; Huber, Cristina; Spiliotis, Markus; Müller, Joachim; Hemphill, Andrew (2014). Profound activity of the anti-cancer drug bortezomib against Echinococcus multilocularis metacestodes identifies the proteasome as a novel drug target for cestodes. PLoS neglected tropical diseases, 8(12), e3352. Public Library of Science 10.1371/journal.pntd.0003352

[img]
Preview
Text
Stadelmann BTZ PLosNTD 2014.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (6MB) | Preview

A library of 426 FDA-approved drugs was screened for in vitro activity against E. multilocularis metacestodes employing the phosphoglucose isomerase (PGI) assay. Initial screening at 20 µM revealed that 7 drugs induced considerable metacestode damage, and further dose-response studies revealed that bortezomib (BTZ), a proteasome inhibitor developed for the chemotherapy of myeloma, displayed high anti-metacestodal activity with an EC50 of 0.6 µM. BTZ treatment of E. multilocularis metacestodes led to an accumulation of ubiquinated proteins and unequivocally parasite death. In-gel zymography assays using E. multilocularis extracts demonstrated BTZ-mediated inhibition of protease activity in a band of approximately 23 kDa, the same size at which the proteasome subunit beta 5 of E. multilocularis could be detected by Western blot. Balb/c mice experimentally infected with E. multilocularis metacestodes were used to assess BTZ treatment, starting at 6 weeks post-infection by intraperitoneal injection of BTZ. This treatment led to reduced parasite weight, but to a degree that was not statistically significant, and it induced adverse effects such as diarrhea and neurological symptoms. In conclusion, the proteasome was identified as a drug target in E. multilocularis metacestodes that can be efficiently inhibited by BTZ in vitro. However, translation of these findings into in vivo efficacy requires further adjustments of treatment regimens using BTZ, or possibly other proteasome inhibitors.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Lundström Stadelmann, Britta; Aeschbacher, Denise; Huber, Cristina; Spiliotis, Markus; Müller, Joachim and Hemphill, Andrew

Subjects:

600 Technology > 630 Agriculture

ISSN:

1935-2727

Publisher:

Public Library of Science

Language:

English

Submitter:

Andrew Hemphill

Date Deposited:

05 Jul 2016 10:21

Last Modified:

15 Jan 2019 09:09

Publisher DOI:

10.1371/journal.pntd.0003352

PubMed ID:

25474446

BORIS DOI:

10.7892/boris.82057

URI:

https://boris.unibe.ch/id/eprint/82057

Actions (login required)

Edit item Edit item
Provide Feedback