Epothilone B induces glioblastoma cell death via survivin down-regulation

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The clinical resistance of glioblastomas to chemotherapeutic agents can be attributed to drug efflux pumps, such as P-glycoprotein, which contributes to reduce drug efficacy. The present study examined the utility of epothilone B, which is not a substrate for P-glycoprotein, on glioblastoma cells. Methods: In vitro methods with glioblastoma cells varying in p53 status were used to assess the efficacy of epothilone B to induce anti-neoplastic responses. Immunofluorescence and ELISA procedures were used to examine levels of tubulin and survivin in epothilone B treated glioblastoma cells, while acridine orange labeling was used to detect the mode of epothilone B induced cell death. Results: A clinically achievable concentration of epothilone B induced a cytotoxic response in p53 mutant glioblastoma cells, as a consequence of survivin down-regulation and tubulin redistribution, while a cytostatic response was observed in p53 null glioblastoma cells with a modest increase in survivin expression post-epothilone B treatment. However, p53 wild-type glioblastoma cells did not sustain a positive anti-tumorigenic response to epothilone B. Conclusion: Epothilone B, induced positive differential responses in glioblastoma cells with abnormal p53 status, but not in p53 wild-type cells. This suggests that epothilone B is a potential alternative to classic microtubule inhibiting agents (ie vincristine, paclitaxel) used to treat clinical glioblastomas with p53 mutations.

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