In vitro efficacy of the anticancer drug imatinib on Echinococcus multilocularis larvae

Hemer, Sarah; Brehm, Klaus

doi:10.1016/j.ijantimicag.2012.07.007

Cited by 62 publications

(55 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Subsequently, the supernatant was removed and sterile filtrated (A4 medium). Inhibitor tests on metacestode vesicles were performed under axenic culture conditions (nitrogen atmosphere [13]) in A4 medium as previously described by Hemer et al [29] and Gelmedin et al [30], with up to ten vesicles per well of a 6-well (5 ml vol. per well) culture plate.…”

Section: Methodsmentioning

confidence: 99%

Targeting Echinococcus multilocularis Stem Cells by Inhibition of the Polo-Like Kinase EmPlk1

Schubert

Koziol

Cailliau³

et al. 2014

PLoS Negl Trop Dis

Self Cite

View full text Add to dashboard Cite

BackgroundAlveolar echinococcosis (AE) is a life-threatening disease caused by larvae of the fox-tapeworm Echinococcus multilocularis. Crucial to AE pathology is continuous infiltrative growth of the parasite's metacestode stage, which is driven by a population of somatic stem cells, called germinative cells. Current anti-AE chemotherapy using benzimidazoles is ineffective in eliminating the germinative cell population, thus leading to remission of parasite growth upon therapy discontinuation.Methodology/Principal findingsWe herein describe the characterization of EmPlk1, encoded by the gene emplk1, which displays significant homologies to members of the Plk1 sub-family of Polo-like kinases that regulate mitosis in eukaryotic cells. We demonstrate germinative cell-specific expression of emplk1 by RT-PCR, transcriptomics, and in situ hybridization. We also show that EmPlk1 can induce germinal vesicle breakdown when heterologously expressed in Xenopus oocytes, indicating that it is an active kinase. This activity was significantly suppressed in presence of BI 2536, a Plk1 inhibitor that has been tested in clinical trials against cancer. Addition of BI 2536 at concentrations as low as 20 nM significantly blocked the formation of metacestode vesicles from cultivated Echinococcus germinative cells. Furthermore, low concentrations of BI 2536 eliminated the germinative cell population from mature metacestode vesicles in vitro, yielding parasite tissue that was no longer capable of proliferation.Conclusions/SignificanceWe conclude that BI 2536 effectively inactivates E. multilocularis germinative cells in parasite larvae in vitro by direct inhibition of EmPlk1, thus inducing mitotic arrest and germinative cell killing. Since germinative cells are decisive for parasite proliferation and metastasis formation within the host, BI 2536 and related compounds are very promising compounds to complement benzimidazoles in AE chemotherapy.

show abstract

Section: Methodsmentioning

confidence: 99%

Targeting Echinococcus multilocularis Stem Cells by Inhibition of the Polo-Like Kinase EmPlk1

Schubert

Koziol

Cailliau³

et al. 2014

PLoS Negl Trop Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…The effects of several drugs inhibiting proliferation of cancer cells were assayed on Echinococcus metacestodes and protoscoleces (3)(4)(5). Spicher et al (4) demonstrated the in vitro and in vivo effects of an endogenous metabolite of estrogen, 2-methoxyestradiol, either alone or combined with albendazole, against Echinococcus multilocularis and E. granulosus.…”

mentioning

confidence: 99%

“…Furthermore, the isoflavone genistein and the genistein derivative Rm6423 exhibited profound in vitro activities against the mentioned parasites (3). The cytostatic drug imatinib had drastic effects on the in vitro development and survival of E. multilocularis (5).…”

mentioning

confidence: 99%

In Vitro and In Vivo Effects of Tamoxifen against Larval Stage Echinococcus granulosus

Nicolao

Elissondo

Denegri

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Cystic echinococcosis is a zoonotic infection caused by the larval stage of the cestodeEchinococcus granulosus. Chemotherapy currently employs benzimidazoles; however, 40% of cases do not respond favorably. With regard to these difficulties, novel therapeutic tools are needed to optimize treatment in humans. The aim of this work was to explore thein vitroandin vivoeffects of tamoxifen (TAM) againstE. granulosus. In addition, possible mechanisms for the susceptibility of TAM are discussed in relation to calcium homeostasis, P-glycoprotein inhibition, and antagonist effects on a putative steroid receptor. After 24 h of treatment, TAM, at a low micromolar concentration range (10 to 50 μM), inhibited the survival ofE. granulosusprotoscoleces and metacestodes. Moreover, we demonstrated the chemotherapeutic and chemopreventive pharmacological effects of the drug. At a dose rate of 20 mg/kg of body weight, TAM induced protection against the infection in mice. In the clinical efficacy studies, a reduction in cyst weight was observed after the administration of 20 mg/kg in mice with cysts developed during 3 or 6 months, compared to that of those collected from control mice. Since the collateral effects of high TAM doses have been largely documented in clinical trials, the use of low doses of this drug as a short-term therapy may be a novel alternative approach for human cystic echinococcosis treatment.

show abstract

“…multilocularis [28, 47–49]. Based on the evolutionary conservation among the kinases of vertebrates and invertebrates (including invertebrate parasites), it has been widely considered that small molecules that target human kinases are promising drug candidates for treating human helminthiasis, including echinococcosis [50–51].…”

Section: Discussionmentioning

confidence: 99%

EGF-mediated EGFR/ERK signaling pathway promotes germinative cell proliferation in Echinococcus multilocularis that contributes to larval growth and development

Cheng

Liu

et al. 2017

PLoS Negl Trop Dis

View full text Add to dashboard Cite

BackgroundLarvae of the tapeworm E. multilocularis cause alveolar echinococcosis (AE), one of the most lethal helminthic infections in humans. A population of stem cell-like cells, the germinative cells, is considered to drive the larval growth and development within the host. The molecular mechanisms controlling the behavior of germinative cells are largely unknown.Methodology/Principal findingsUsing in vitro cultivation systems we show here that the EGFR/ERK signaling in the parasite can promote germinative cell proliferation in response to addition of human EGF, resulting in stimulated growth and development of the metacestode larvae. Inhibition of the signaling by either the EGFR inhibitors CI-1033 and BIBW2992 or the MEK/ERK inhibitor U0126 impairs germinative cell proliferation and larval growth.Conclusions/SignificanceThese data demonstrate the contribution of EGF-mediated EGFR/ERK signaling to the regulation of germinative cells in E. multilocularis, and suggest the EGFR/ERK signaling as a potential therapeutic target for AE and perhaps other human cestodiasis.

show abstract

In vitro efficacy of the anticancer drug imatinib on Echinococcus multilocularis larvae

Cited by 62 publications

References 14 publications

Targeting Echinococcus multilocularis Stem Cells by Inhibition of the Polo-Like Kinase EmPlk1

Targeting Echinococcus multilocularis Stem Cells by Inhibition of the Polo-Like Kinase EmPlk1

In Vitro and In Vivo Effects of Tamoxifen against Larval Stage Echinococcus granulosus

EGF-mediated EGFR/ERK signaling pathway promotes germinative cell proliferation in Echinococcus multilocularis that contributes to larval growth and development

Contact Info

Product

Resources

About