The role of the cytoskeletal protein, tubulin, in the mode of action and mechanism of drug resistance to benzimidazoles

Lacey, Ernest

doi:10.1016/0020-7519(88)90175-0

Cited by 506 publications

(263 citation statements)

References 204 publications

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“…The average reported peak serum concentration after a single dose of mebendazole used as an antiparasitic agent in the treatment of hydatid disease is 1.67 Amol/L (16), whereas we found striking effects using concentrations in the clinically relevant range of 0.5 to 1 Amol/L. Mebendazole has been extensively used to treat gastrointestinal parasitic infections in humans, and in this capacity, it has shown remarkable efficacy and safety (17,18). Furthermore, clinical data from long-term mebendazole therapy in the treatment of alveolar echinococcosis suggest that mebendazole should also exhibit minimal toxicity when used as a cancer therapy (19,20).…”

Section: Discussionmentioning

confidence: 69%

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Doudican¹,

Rodriguez²,

Osman

et al. 2008

Molecular Cancer Research

128

114

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Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 Mmol/L using two chemoresistant melanoma cell lines ) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC 50 of 0.32 Mmol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent. (Mol Cancer Res 2008;6(8):1308 -15)

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Section: Discussionmentioning

confidence: 69%

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Doudican¹,

Rodriguez²,

Osman

et al. 2008

Molecular Cancer Research

128

114

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“…This broad spectrum anthelmintic inhibits the cell division of parasites by binding to tubulin monomers. This binding prevents the self-polymerization of monomers leading to microtubule instability (Lacey 1988;Lubega and Prichard 1990). Initially, BZ group of drugs were highly efficacious in controlling helminth parasites affecting domestic animals.…”

Section: Introductionmentioning

confidence: 99%

Genotyping of benzimidazole resistant and susceptible isolates of Haemonchus contortus from sheep by allele specific PCR

et al. 2016

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Extensive and indiscriminate use of the benzimidazole class of drugs has led to the onset of anthelmintic resistance. In tropical countries like India, Haemonchus contortus is the most pathogenic parasite infecting sheep and goats. The widespread presence of resistant helminths (especially H. contortus) threatens the livestock farming. The use of various drugs has led to single nucleotide polymorphism that causes specific amino acid substitutions in b-tubulin protein of H. contortus to confer resistance. This emphasizes the need for a survey on the present status of resistance in India. In this study, allele specific PCR was employed to screen the presence of a SNP, a thymine-toadenine transversion which leads to substitution of amino acid in codon 200 of b-tubulin gene that is correlated specifically with BZ resistance. Third stage larvae (L3) from pooled faecal cultures of four organized sheep farms served as a source of genomic DNA for identification of H. contortus and further genotype analysis. A total of 1000 larvae was screened, out of which 673 larvae were identified as H. contortus. Among 673 H. contortus larvae, 539 larvae (80 %) were genotyped as homozygous resistant (rr) and remaining 134 (20 %) were heterozygous susceptible (Sr) by allele specific PCR. The concluded resistance status reasons out the failure of anthelmintic drug in treating ruminants. Immediate steps are needed to avoid further aggravation of the problem. Target selective treatment by reviewing the resistance status of individual drugs, appropriate use of anthelmintic drugs and other control strategies will provide a pragmatic option for delaying the further spread of anthelmintic resistance.

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“…Anticancer activities of several anthelminthics attracted considerable interest, especially their capacity to target signal transduction pathways of CSCs/TICs of several tumor types. Aside of the inhibition of signal transduction, on-target repositioning assumes that the targets recognized in nematods, such as mitochondrial respiration and microtubules, are hit in cancer cells [70,89,90]. However, the multitude of effects observed in response to the anthelminthics cannot be explained by specific and defined intracellular targets.…”

Section: Resultsmentioning

confidence: 99%

Repurposing of Anthelminthics as Anticancer Drugs

Hamilton¹,

Rath²

2018

Oncomedicine

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The role of the cytoskeletal protein, tubulin, in the mode of action and mechanism of drug resistance to benzimidazoles

Cited by 506 publications

References 204 publications

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Genotyping of benzimidazole resistant and susceptible isolates of Haemonchus contortus from sheep by allele specific PCR

Repurposing of Anthelminthics as Anticancer Drugs

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