Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma.
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 combination 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.
Bilir
Ayhan
A
Department of Histology and Embryology, Istanbul University, Istanbul Faculty of Medicine, 34093 Capa, Istanbul, Turkey. bilira@istanbul.edu.tr
Erguven
Mine
M
Oktem
Gulperi
G
Ozdemir
Aysegul
A
Uslu
Atilla
A
Aktas
Esin
E
Bonavida
Benjamin
B
D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002997:Clomipramine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000032:analysis; D004357:Drug Synergism; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D000068877:Imatinib Mesylate; D008855:Microscopy, Electron, Scanning; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats
D017304:Annexin A5; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000242:Cyclic AMP; D001973:Bromodeoxyuridine; D002997:Clomipramine