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

Abstract

AIM:

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.

• Authors: Q A Quick
• Journal: Experimental oncology (Exp Oncol) Vol. 30 Issue 3 Pg. 195-201 (Sep 2008) ISSN: 1812-9269 [Print] Ukraine
• PMID: 18806741 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• BIRC5 protein, human
• Epothilones
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• Survivin
• TP53 protein, human
• Tubulin
• Tubulin Modulators
• Tumor Suppressor Protein p53
• Gentian Violet
• epothilone B

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation
• Down-Regulation
• Enzyme-Linked Immunosorbent Assay
• Epothilones (pharmacology)
• Fluorescent Antibody Technique
• Gentian Violet
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins (metabolism)
• Mutation (genetics)
• Neoplasm Proteins (metabolism)
• Survivin
• Tubulin (metabolism)
• Tubulin Modulators (pharmacology)
• Tumor Cells, Cultured
• Tumor Stem Cell Assay
• Tumor Suppressor Protein p53 (genetics, metabolism)