科研之友
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摘要
Beta-sitosterol (beta-SITO), a phytosterol present in many edible vegetables, has been reported to possess antineoplastic properties and cancer treatment potential. We have shown previously that it binds at a unique site (the SITO-site') compared to the colchicine binding site at the interface of alpha- and beta-tubulin. In this study, we investigated the anticancer efficacy of beta-SITO against invasive breast carcinoma using MCF-7 cells. Since isotypes' of beta-tubulin show tissue-specific expression and many are associated with cancer drug resistance, using computer-assisted docking and atomistic molecular dynamic simulations, we also examined its binding interactions to all known isotypes of beta-tubulin in alpha beta-tubulin dimer. beta-SITO inhibited MCF-7 cell viability by up to 50%, compared to vehicle-treated control cells. Indicating its antimetastatic potential, the phytosterol strongly inhibited cell migration. Immunofluorescence imaging of beta-SITO-treated MCF-7 cells exhibited disruption of the microtubules and chromosome organization. Far-UV circular dichroism spectra indicated loss of helical stability in tubulin when bound to beta-SITO. Docking and MD simulation studies, combined with MM-PBSA and MM-GBSA calculations revealed that beta-SITO preferentially binds with specific beta-tubulin isotypes (beta(II) and beta(III)) in the alpha beta-tubulin dimer. Both these beta-tubulin isotypes have been implicated in drug resistance against tubulin-targeted chemotherapeutics. Our data show the tubulin-targeted anticancer potential of beta-SITO, and its potential clinical utility against beta(II) and beta(III) isotype-overexpressing neoplasms.
- 出版日期2018
