Inhibitors of EGFR Signaling Retard Cytotoxicity of Fenretinide in Rat Gliosarcoma Cells

• Published in: Neurochemical research 2008, Vol.33 (1), p.22-26
• Main Authors: Zaheer, Ayesha, Sahu, Shailendra K., Traynelis, Vincent C.
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Line, Tumor; Fenretinide - pharmacology; Neurochemistry; Neurology; Neurosciences; Original Paper; Rats; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction - drug effects
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-007-9401-2

Purpose Fenretinide, 4-( N -hydroxyphenyl) retinamide, (4-HPR) is a well tolerated analog of alltrans retinoic acid. The gangliosideGM3, is a non-specific inhibitor of EGF receptor autophosphorylation (EGFR-phos). Both compounds were found preferentially cytotoxic to malignant and proliferating cells when compared to non-proliferating normal brain cells. Some of the small molecule inhibitors of EGFR-phos are also known to inhibit growth of brain tumors at relatively non-toxic doses. The purpose of this investigation was to evaluate if 4-HPR and inhibitors of EGFR-phos could be used together in the treatment of brain tumors. Methods The 9L rat gliosarcoma cells were treated in vitro with 4-HPR either alone or in combination with the non-specific or specific inhibitors of EGFR-phos, GM3 or AG-1478, respectively. The relative viability of the control and treated cells was determined using 3-(4,5-imethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The experimental data were analyzed for statistical significance. Results In contrast to the expected additive/synergistic effect on cell growth inhibition, the sub-toxic and toxic concentrations of 4-HPR protected GM3 treated cells. The viable cells were 3.86 times higher following GM3 plus 4-HPR treatments compared to GM3 treatment alone. Additionally, a specific inhibitor of EGFR-phos signaling, AG-1478 caused a concentration dependent protection of cells from the toxicity of 4-HPR. Our results show counteracting cytotoxic responses of 4-HPR and EGFR-phos inhibitors when used together in 9L rat gliosarcoma cells.