P-glycoproteins play a role in ivermectin resistance in cyathostomins

Peachey, Laura; Pinchbeck, Gina; Matthews, Jonathan C. F.; Burden, Faith; Lespine, Anne; Samson‐Himmelstjerna, Georg von; Krücken, Jürgen; Hodgkinson, Jane E.

doi:10.1016/j.ijpddr.2017.10.006

Cited by 29 publications

(26 citation statements)

References 81 publications

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“…The different effects of IVM on P-gp expression in mouse hepatocytes, intestinal cells, and human cancer cells may be due to the difference of tissues, animal species, and the drug doses used. Also, there were several reports showing that the anti-parasitic drug IVM was the P-gp substrate, and P-gp played a role in the IVM resistance in parasites and altered function of P-gp in blood-brain barrier would result in severe IVM-induced neurotoxicity [44–46]. In our study, we indeed found that IVM inhibited P-gp function (Fig.…”

Section: Discussionsupporting

confidence: 78%

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

Jiang

Wang

Sun

et al. 2019

J Exp Clin Cancer Res

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Background Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. In this study, we sought to explore whether ivermectin (IVM), a macrolide antiparasitic agent, could overcome the resistance of cancer cells to the therapeutic drugs. Methods We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 breast cancer cells) and one hematologic tumor cell line (K562 chronic myeloid leukemia cells), which are resistant to the chemotherapeutic drugs vincristine and adriamycin respectively, and two xenograft mice models, including the solid tumor model in nude mice with the resistant HCT-8 cells and the leukemia model in NOD/SCID mice with the resistant K562 cells to investigate the reversal effect of IVM on the resistance in vitro and in vivo . MTT assay was used to investigate the effect of IVM on cancer cells growth in vitro . Flow cytometry, immunohistochemistry, and immunofluorescence were performed to investigate the reversal effect of IVM in vivo . Western blotting, qPCR, luciferase reporter assay and ChIP assay were used to detect the molecular mechanism of the reversal effect. Octet RED96 system and Co-IP were used to determine the interactions between IVM and EGFR. Results Our results indicated that ivermectin at its very low dose, which did not induce obvious cytotoxicity, drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo . Mechanistically, ivermectin reversed the resistance mainly by reducing the expression of P-glycoprotein (P-gp) via inhibiting the epidermal growth factor receptor (EGFR), not by directly inhibiting P-gp activity. Ivermectin bound with the extracellular domain of EGFR, which inhibited the activation of EGFR and its downstream signaling cascade ERK/Akt/NF-κB. The inhibition of the transcriptional factor NF-κB led to the reduced P-gp transcription. Conclusions These findings demonstrated that ivermectin significantly enhanced the anti-cancer efficacy of chemotherapeutic drugs to tumor cells, especially in the drug-resistant cells. Thus, ivermectin, a FDA-approved antiparasitic drug, could potentially be used in combination with chemotherapeutic agents to treat cancers and in particular, the drug-resistant cancers. Electronic supplementary material The online version of this article (10.1186/s13046-019-1251-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 78%

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

Jiang

Wang

Sun

et al. 2019

J Exp Clin Cancer Res

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“…In addition to CYPs and UGTs, the effect of ABZ and ABZSO on expression of efflux transporters P-glycoproteins (P-gps) was also studied as P-gps have been implicated in the multidrug resistance of different parasitic nematodes in livestock [14]. Although the increased transcription of P-gps has been mainly associated with resistance to IVM and other macrocyclic lactones [37,38], the participation of P-gps in ABZ resistance cannot be excluded. In our study, exposure to ABZ and ABZSO affected transcription levels of six (out of eight tested) transporter genes in H. contortus adults.…”

Section: Discussionmentioning

confidence: 99%

Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults

Kellerová¹,

Stuchlíková²,

Matoušková³

et al. 2020

Vet Res

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The efficacy of anthelmintic therapy of farm animals rapidly decreases due to drug resistance development in helminths. In resistant isolates, the increased expression and activity of drug-metabolizing enzymes (DMEs), e.g. cytochromes P450 (CYPs), UDP-glycosyltransferases (UGTs) and P-glycoprotein transporters (P-gps), in comparison to sensitive isolates have been described. However, the mechanisms and circumstances of DMEs induction are not well known. Therefore, the present study was designed to find the changes in expression of CYPs, UGTs and P-gps in adult parasitic nematodes Haemonchus contortus exposed to sub-lethal doses of the benzimidazole anthelmintic drug albendazole (ABZ) and its active metabolite ABZ-sulfoxide (ABZSO). In addition, the effect of ABZ at sub-lethal doses on the ability to deactivate ABZ during consequent treatment was studied. The results showed that contact of H. contortus adults with sub-lethal doses of ABZ and ABZSO led to a significant induction of several DMEs, particularly cyp-2, cyp-3

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“…P-gp, encoded by the Abcb1 gene, belongs to the family of adenosine triphosphate (ATP)-binding cassette transporters and is usually localized in excretory and barrier-function tissues, such as the kidney and intestine [6,7]. P-gp can utilize the hydrolysis of ATP to energize the efflux of a broad range of substrates, including commonly used antimicrobial agents licensed in veterinary medicine (e.g., ivermectin, enrofloxacin, and danofloxacin) [8,9,10], influencing the absorption, distribution, and excretion of substrates [11]. Therefore, overcoming P-gp efflux is a strategy to improve the absorption and pharmacokinetics of substrates.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effect of Berberine on Broiler P-glycoprotein Expression and Function: In Situ and In Vitro Studies

Zhang

Guo

Huang

et al. 2019

IJMS

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Overcoming P-glycoprotein (P-gp) efflux is a strategy to improve the absorption and pharmacokinetics of its substrate drugs. Berberine inhibits P-gp and thereby increases the bioavailability of the P-gp substrate digoxin in rodents. However, the effects of berberine on P-gp in chickens are still unclear. Here, we studied the role of berberine in modulating broilers P-gp expression and function through both in situ and in vitro models. In addition, molecular docking was applied to analyze the interactions of berberine with P-gp as well as with chicken xenobiotic receptor (CXR). The results showed that the mRNA expression levels of chicken P-gp and CXR decreased in the ileum following exposure to berberine. The absorption rate constant of rhodamine 123 increased after berberine treatment, as detected using an in situ single-pass intestinal perfusion model. Efflux ratios of P-gp substrates (tilmicosin, ciprofloxacin, clindamycin, ampicillin, and enrofloxacin) decreased and the apparent permeability coefficients increased after co-incubation with berberine in MDCK-chAbcb1 cell models. Bidirectional assay results showed that berberine could be transported by chicken P-gp with a transport ratio of 4.20, and this was attenuated by verapamil (an inhibitor of P-gp), which resulted in a ratio of 1.13. Molecular docking revealed that berberine could form favorable interactions with the binding pockets of both CXR and P-gp, with docking scores of −7.8 and −9.5 kcal/mol, respectively. These results indicate that berberine is a substrate of chicken P-gp and down-regulates P-gp expression in chicken tissues, thereby increasing the absorption of P-gp substrates. Our findings suggest that berberine increases the bioavailability of other drugs and that drug-drug interactions should be considered when it is co-administered with other P-gp substrates with narrow therapeutic windows.

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P-glycoproteins play a role in ivermectin resistance in cyathostomins

Cited by 29 publications

References 81 publications

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway

Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults

Inhibitory Effect of Berberine on Broiler P-glycoprotein Expression and Function: In Situ and In Vitro Studies

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