Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro

Raza, Ali; Kopp, Steven; Jabbar, Abdul; Kotze, Andrew C.

doi:10.1016/j.vetpar.2015.04.025

Cited by 33 publications

(53 citation statements)

References 43 publications

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“…The Kirby larvae showed increased sensitivity to crizotinib in both the LMA and LDA compared to WAL, with dose-response curves shifted to the left for Kirby compared to WAL, and hence lower combination treatment crizotinib concentrations were selected for subsequent combination assays with Kirby compared to WAL. It has previously been 9 reported that WAL larvae tolerate higher levels of some MDRIs than Kirby larvae, for example verapamil and zosuquidar (Raza et al, 2015). The present study and our earlier data therefore suggest that WAL larvae may have defensive systems that allow them to survive in the presence of higher concentrations of crizotinib and other MDRIs.…”

Section: Resultssupporting

confidence: 71%

“…This suggestion of no role in resistance in the early larval stages needs to be tempered by the fact that crizotinib may only interact with a sub-set of the ABC transporters present in nematode larvae, or at least its inhibitory effects may vary across the population of ABC transporters, and hence it is only the lack of a role for the specific ABC transporters inhibited by this compound that is indicated by the data for early stage larvae. Raza et al (2015) also found that the synergistic effects of a number of MDRI were more marked in larval migration assays compared to LDAs; for example co-administration of zosuquidar and tariquidar rendered the WAL larvae more sensitive to IVM than Kirby larvae (synergism ratios 4.7-6.0), whereas these compounds had less effect on the toxicity of IVM towards WAL larvae in LDAs (SRs 1.6-2.4).…”

Section: Resultsmentioning

confidence: 90%

“…All animal procedures were approved by the FD McMaster Animal Ethics Committee, CSIRO Agriculture (Animal Ethics Approval Number AEC 13/23). Worm eggs and infective stage L3 larvae were prepared for use in larval development and migration assays, respectively, as described previously (Raza et al, 2015).…”

Section: Parasites and Chemicalsmentioning

confidence: 99%

“…The ability of ivermectin, alone or in combination with crizotinib, to inhibit the migration of L3 stage larvae through an agar/mesh system was measured using a larval migration assay (LMA) in 96-well microtitre plates (Kotze et al, 2006), as described previously (Raza et al, (2015). Final concentration ranges for IVM were 25000-195.30 ng/mL for WAL, while the ranges used for Kirby were 6250-48.8 ng/mL (final DMSO concentration was 1% v/v).…”

Section: Worm Bioassaysmentioning

confidence: 99%

“…Numerous in vitro and in vivo studies have shown that an anthelmintic/ MDRI combination therapy increases the toxicity of the anthelmintic to both drug-susceptible and -resistant isolates of different nematode species (Bartley et al, 2009;Pérez et al, 2010;Heckler et al, 2014). Recently, Raza et al (2015) reported that zosuquidar and tariquidar, members of the so-called third generation of MDRIs (Falasca and Linton, 2012) significantly increased ivermectin (IVM) toxicity to Haemonchus contortus larvae in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Synergism between ivermectin and the tyrosine kinase/ P -glycoprotein inhibitor crizotinib against Haemonchus contortus larvae in vitro

Raza

Kopp

Kotze

2016

Veterinary Parasitology

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2 Graphical abstract3 Highlights:-we examined interaction of P-gp inhibitor crizotinib with ivermectin in Haemonchus contortus larvae in vitro -crizotinib increased the toxicity of ivermectin towards a resistant isolate in migration assays -less synergism observed in larval development assays -assay differences suggest life-stage specific patterns of ivermectin / P-gp interaction.-study highlights potential of P-gp inhibitors to reverse ivermectin resistance AbstractAnthelmintic resistance is a major problem in parasitic nematodes of livestock worldwide. One means to counter resistance is to use synergists that specifically inhibit resistance mechanisms in order to restore the toxicity, and hence preserve the usefulness, of currently available anthelmintics. P-glycoproteins (P-gps) eliminate a wide variety of structurally unrelated xenobiotics from cells, and have been implicated in anthelmintic resistance. Crizotinib is a tyrosine kinase inhibitor under development as a cancer therapeutic.The compound also inhibits P-gps, and has been shown to reverse multidrug resistance in cancer cells. We were therefore interested in determining if the compound was able to increase the sensitivity of Haemonchus contortus larvae to ivermectin, as measured by in vitro larval development and migration assays with a drug-resistant and a -susceptible isolate. In migration assays, co-administration of crizotinib increased the toxicity of ivermectin to resistant larvae (up to 5.7-fold decrease in ivermectin IC50), and rendered the resistant larvae equally or more sensitive to ivermectin than the susceptible isolate. On the other hand, co-administration of crizotinib had no effect on ivermectin sensitivity in the 4 susceptible isolate. In development assays, significant increases in the sensitivity of both the resistant (up to 1.9-fold) and susceptible (up to 1.6-fold) larvae to ivermectin were observed , although the magnitude of the observed synergism was less than seen in migration assays, and the resistant larvae retained significant levels of ivermectin resistance. By highlighting the ability of the P-gp inhibitor crizotinib to increase the sensitivity of H. contortus larvae to ivermectin, this study provides further evidence that P-gp inhibitors are potential tools for modulating the efficacy of anthelmintics. In addition, the differences in the outcomes of the two assays, with 'resistance-breaking' effects being much more marked in migration assays, suggest that some life-stage-specific aspects may exist in the interaction of ivermectin with Pgps in the two worm isolates.

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 90%

Section: Parasites and Chemicalsmentioning

confidence: 99%

Section: Worm Bioassaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synergism between ivermectin and the tyrosine kinase/ P -glycoprotein inhibitor crizotinib against Haemonchus contortus larvae in vitro

Raza

Kopp

Kotze

2016

Veterinary Parasitology

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Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy

Cao,

Zhang,

Zhou

et al. 2023

MedComm

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Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP‐binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance‐associated protein 1 (MRP1), and breast cancer‐resistant protein (BCRP), in drug‐resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.

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Drug Resistance in Nematodes

Prichard¹

2017

Antimicrobial Drug Resistance

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Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro

Cited by 33 publications

References 43 publications

Synergism between ivermectin and the tyrosine kinase/ P -glycoprotein inhibitor crizotinib against Haemonchus contortus larvae in vitro

Synergism between ivermectin and the tyrosine kinase/ P -glycoprotein inhibitor crizotinib against Haemonchus contortus larvae in vitro

Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy

Drug Resistance in Nematodes

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