Epothilone B induces glioblastoma cell death via survivin down-regulation.
OBJECTIVE
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.


CONCLUSIONS
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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Department of Biological Sciences, Grambling State University, Grambling, LA 71245, USA. quickq@gram.edu
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D034261:Epothilones / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D005840:Gentian Violet; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism; D000077022:Survivin; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C107489:BIRC5 protein, human; D034261:Epothilones; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; C495901:TP53 protein, human; D014404:Tubulin; D050257:Tubulin Modulators; D016159:Tumor Suppressor Protein p53; D005840:Gentian Violet; C093788:epothilone B