Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma

  • Authors:
    • Ayhan Bilir
    • Mine Erguven
    • Gulperi Oktem
    • Aysegul Ozdemir
    • Atilla Uslu
    • Esin Aktas
    • Benjamin Bonavida
  • View Affiliations

  • Published online on: April 1, 2008     https://doi.org/10.3892/ijo.32.4.829
  • Pages: 829-839
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Abstract

Rat C6 glioma is a chemo-resistant experimental brain tumor that is difficult to treat with various drug combinations. Previous studies suggested that imatinib mesylate (Gleevec) is effective in pre-clinical trials for glioblastoma. Also, chlorimipramine (Anafranil) is an anti-depressant drug in use in the clinic and shown to have anti-neoplastic activity. We hypothesized that treatment of resistant C6 glioma with combination of imatinib and chlorimipramine may potentiate cytotoxicity and reverse resistance. C6 glioma was examined both as monolayer and as spheroid cultures. Several experimental designs were examined all of which showed synergistic activity albeit at different time kinetics. Combination treatment resulted in inhibition of cell growth and enhanced cell death as determined by dye exclusion. Further, the combination treatment resulted in significant induction of apoptosis as determined by Annexin V-FITC and PI. Also, there was inhibition of DNA synthesis and cAMP. Altogether, these findings supported the anti-proliferative and cytotoxic effects of the combination treatment. Morphological studies were also performed using transmission and scanning electron microscopy. Significant synergistic apoptosis was detected by the combination treatment in both the monolayers and spheroid cultures. There was also a synergistic effect in autophagy by the combination. Several altered morphological features were noted by both the individual compound and enhanced by the combination treatment. The present findings support our hypothesis and demonstrate the potentiation of cytotoxicity by the com-bination of imatinib and chlorimipramine in C6 glioma. Further, the findings suggest the potential clinical application of the combination in the treatment of drug-resistant glioma.

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April 2008
Volume 32 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Bilir A, Erguven M, Oktem G, Ozdemir A, Uslu A, Aktas E and Bonavida B: Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma. Int J Oncol 32: 829-839, 2008.
APA
Bilir, A., Erguven, M., Oktem, G., Ozdemir, A., Uslu, A., Aktas, E., & Bonavida, B. (2008). Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma. International Journal of Oncology, 32, 829-839. https://doi.org/10.3892/ijo.32.4.829
MLA
Bilir, A., Erguven, M., Oktem, G., Ozdemir, A., Uslu, A., Aktas, E., Bonavida, B."Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma". International Journal of Oncology 32.4 (2008): 829-839.
Chicago
Bilir, A., Erguven, M., Oktem, G., Ozdemir, A., Uslu, A., Aktas, E., Bonavida, B."Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma". International Journal of Oncology 32, no. 4 (2008): 829-839. https://doi.org/10.3892/ijo.32.4.829