Elucidation of the anticancer potential and tubulin isotype-specific interactions of β-sitosterol.

Abstract

Beta-sitosterol (β-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 α- and β-tubulin. In this study, we investigated the anticancer efficacy of β-SITO against invasive breast carcinoma using MCF-7 cells. Since 'isotypes' of β-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 β-tubulin in αβ-tubulin dimer. β-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 β-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 β-SITO. Docking and MD simulation studies, combined with MM-PBSA and MM-GBSA calculations revealed that β-SITO preferentially binds with specific β-tubulin isotypes (βII and βIII) in the αβ-tubulin dimer. Both these β-tubulin isotypes have been implicated in drug resistance against tubulin-targeted chemotherapeutics. Our data show the tubulin-targeted anticancer potential of β-SITO, and its potential clinical utility against βII and βIII isotype-overexpressing neoplasms.

• Authors: Madhura Pradhan, Charu Suri, Sinjan Choudhary, Pradeep Kumar Naik, Manu Lopus
• Journal: Journal of biomolecular structure & dynamics (J Biomol Struct Dyn) Vol. 36 Issue 1 Pg. 195-208 (01 2018) ISSN: 1538-0254 [Electronic] England
• PMID: 27960611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Sitosterols
• Tubulin
• gamma-sitosterol

Topics

• Antineoplastic Agents (chemistry, metabolism)
• Binding Sites
• Breast Neoplasms (metabolism, pathology)
• Female
• Humans
• MCF-7 Cells
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Molecular Structure
• Protein Binding
• Protein Domains
• Protein Multimerization
• Sitosterols (chemistry, metabolism)
• Tubulin (chemistry, metabolism)