Abstract
BackgroundAnti-mitotic compounds (microtubule de-stabilizers) such as vincristine and vinblastine have been shown clinically successful in treating various cancers. However, development of drug-resistance cells limits their efficacies in clinical situations. Therefore, experiments were performed to determine possible drug resistance mechanisms related to the application of anti-mitotic cancer therapy.Principal FindingsA KB-derived microtubule de-stabilizer-resistant KB-L30 cancer cell line was generated for this study. KB-L30 cells showed cross-resistance to various microtubule de-stabilizers including BPR0L075, vincristine and colchicine through multiple-drug resistant (MDR)-independent mechanisms. Surprisingly, KB-L30 cells showed hyper-sensitivity to the microtubule-stabilizer, paclitaxel. Results of the RT-PCR analysis revealed that expression of both class II and III β-tubulin was down-regulated in KB-L30 cells as compared to its parental KB cancer cells. In addition, DNA sequencing analysis revealed six novel mutation sites present in exon four of the βI-tubulin gene. Computational modeling indicated that a direct relationship exists between βI-tubulin mutations and alteration in the microtubule assembly and dynamic instability in KB-L30 cells and this predicted model was supported by an increased microtubule assembly and reduced microtubule dynamic instability in KB-L30 cells, as shown by Western blot analysis.Conclusions and SignificanceOur study demonstrated that these novel mutations in exon four of the βI-tubulin induced resistance to microtubule de-stabilizers and hyper-sensitivity to microtubule stabilizer through an alteration in the microtubule assembly and dynamics in cancer cells. Importantly, the current study reveals that cancer cells may acquire drug resistance ability to anti-mitotic compounds through multiple changes in the microtubule networks. This study further provided molecular information in drug selection for patients with specific tubulin mutations.
Highlights
Microtubules are protein filaments of the cytoskeleton composed of a-tubulin and b-tubulin molecules
Our study demonstrated that these novel mutations in exon four of the bI-tubulin induced resistance to microtubule de-stabilizers and hyper-sensitivity to microtubule stabilizer through an alteration in the microtubule assembly and dynamics in cancer cells
The current study reveals that cancer cells may acquire drug resistance ability to anti-mitotic compounds through multiple changes in the microtubule networks
Summary
Microtubules are protein filaments of the cytoskeleton composed of a-tubulin and b-tubulin molecules. Anti-mitotic compounds such as vincristine, vinblastine (microtubule-destabilizing Vinca alkaloid) and paclitaxel (microtubule-stabilizing taxane) have been developed to target cancers clinically [2,3]. The taxanes and Vinca alkaloids are effective for the management of different malignancies, their potential is limited by the development of multidrug resistance (MDR) [4,5]. Besides the expression of MDR, additional mechanisms of resistance to anti-mitotic drugs have been described previously. These include changes in tubulin isotype expression and mutations in the. Anti-mitotic compounds (microtubule de-stabilizers) such as vincristine and vinblastine have been shown clinically successful in treating various cancers. Development of drug-resistance cells limits their efficacies in clinical situations. Experiments were performed to determine possible drug resistance mechanisms related to the application of anti-mitotic cancer therapy
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