The effects of taxanes, vorinostat and doxorubicin on growth and proliferation of Echinococcus multilocularis metacestodes assessed with magnetic resonance imaging and simultaneous positron emission tomography

Abstract

Cytostatic drugs used in cancer therapy were evaluated for their capacity to inhibit Echinococcus multilocularis metacestode growth and proliferation. Metacestode tissues were exposed in vitro to docetaxel, doxorubicin, navelbine, paclitaxel, and vorinostat for 1 week, then incubated in drug-free culture, and thereafter metacestodes were injected into the peritoneum of Meriones unguiculatus. Magnetic resonance imaging (MRI) and simultaneous positron emission tomography (PET) were applied to monitor in vivo growth of drug-exposed E. multilocularis in Meriones. At 3 month p.i., docetaxel (at 10 μM, 5 μM and 2 μM) inhibited in vivo growth and proliferation of E. multilocularis, and at 5 months p.i., only in the 2 μM docetaxel exposure group 0.3 cm3 of parasite tissue was found. With paclitaxel and navelbine the in vivo growth of metacestodes was suppressed until 3 months p.i., thereafter, parasite tissues enlarged up to 3 cm3 in both groups. E. multilocularis tissues of more than 10 g developed in Meriones injected with metacestodes which were previously exposed in vitro to doxorubicin, navelbine, paclitaxel or vorinostat. In Meriones infected with metacestodes previously exposed to docetaxel, the in vivo grown parasite tissues weighted 0.2 g. In vitro cultured E. multilocularis metacestodes exposed to docetaxel did not produce vesicles until 7 weeks post drug exposure, while metacestodes exposed to doxorubicin, navelbine and vorinostat proliferated continuously. In summary, docetaxel, and less efficaciously paclitaxel, inhibited in vivo and in vitro parasite growth and proliferation, and these observations suggest further experimental studies with selected drug combinations which may translate into new treatment options against alveolar echinococcosis.

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

“…Nevertheless, such drugs are a promising starting point for screening approaches with limited resources, and potentially allow to gain more insights about their possible modes of action and thus potentially valuable targets where research should be focused. Most studies on drug repurposing against AE evaluated an overall relatively small number of compounds, including anti-cancer compounds ( Naguleswaran et al, 2006 ; Gelmedin et al, 2008 , 2010 ; Spicher et al, 2008a ; Hübner et al, 2010 ; Hemer and Brehm, 2012 ; Schubert et al, 2014 ; Huang et al, 2018 ; Joekel et al, 2018 ; Förster et al, 2019 ), anti-infective drugs ( Reuter et al, 2003 , 2006 ; Stettler et al, 2003 ; Spicher et al, 2008b ; Stadelmann et al, 2010 , 2011 ; Küster et al, 2011 , 2014a , 2014b , 2015 ; Rufener et al, 2018a , 2018b ), immunotherapeutics ( Emery et al, 1998 ; Pfister et al, 1989 ; Godot et al, 2003 ; Boubaker et al, 2015 ; Wang et al, 2018 ; Jebbawi et al ), and natural products ( Albani Clara and Elissondo María, 2014 ; Albani et al, 2015 ; Yuan et al, 2016 ; Hizem et al, 2019 ). In the following sections, we will focus more on anti-infective drugs, and in particular on the group of anti-malarials.…”

New Uses for Old Drugs and Their Application in Helminthology

“…After, magnetic resonance imaging and simultaneous positron emission tomography were applied to monitor in vivo growth of drug-exposed Echinococcus multilocularis. The in vivo growth of metacestodes was suppressed until 3 months postinfection, thereafter, parasite tissues enlarged up to 3 cm 3 [51].…”

“…Finally, in an in vitro cyst incubation it was shown that paclitaxel resulted in dramatic alterations within 3 to 5 days after initiation of treatment [50]. In another experiment, Huang et al (2018) evaluated the effect of paclitaxel on growth and proliferation of Echinococcus multilocularis metacestodes. They exposed metacestode tissues in vitro to paclitaxel (2, 5, and 10 μM) for one week and, thereafter, were injected into the peritoneum of Meriones unguiculatus.…”

“…The only report where the effect of docetaxel against a helminth has been evaluated was carried out by Huang et al (2018). They report that at three months postinfection, docetaxel (at 10 μM, 5 μM and 2 μM) inhibited in vivo growth and proliferation of Echinococcus multilocularis, and at 5 months postinfection, only in the 2 μM docetaxel exposure group 0.3 cm 3 of parasite tissue was found [51].…”

“…The only report where the effect of docetaxel against a helminth has been evaluated was carried out by Huang et al (2018). They report that at three months postinfection, docetaxel (at 10 μM, 5 μM and 2 μM) inhibited in vivo growth and proliferation of Echinococcus multilocularis, and at 5 months postinfection, only in the 2 μM docetaxel exposure group 0.3 cm 3 of parasite tissue was found [51]. Moreover, in Meriones infected with Echinococcus multilocularis metacestodes previously exposed to docetaxel, in vivo grown parasite tissues weighed 0.2 g and in vitro cultured Echinococcus multilocularis metacestodes exposed to docetaxel did not produce vesicles until 7 weeks post-drug exposure.…”