Neurochemical Research

, Volume 33, Issue 1, pp 22–26 | Cite as

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

  • Ayesha Zaheer
  • Shailendra K. Sahu
  • Vincent C. Traynelis
Original Paper


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.


Fenretinide EGFR Monosialganglioside AG-1478 Gliosarcoma Cytotoxicity 



The internal funding from the Department of Neurosurgery, UIHC, IOWA City, Iowa, supported this work.


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Ayesha Zaheer
    • 1
  • Shailendra K. Sahu
    • 1
  • Vincent C. Traynelis
    • 1
  1. 1.Department of NeurosurgeryUniversity of Iowa Hospitals and ClinicsIowa CityUSA

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