Inhibitors of EGFR Signaling Retard Cytotoxicity of Fenretinide in Rat Gliosarcoma Cells
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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.
KeywordsFenretinide EGFR Monosialganglioside AG-1478 Gliosarcoma Cytotoxicity
The internal funding from the Department of Neurosurgery, UIHC, IOWA City, Iowa, supported this work.
- 8.Lovat PE, Di Sano F, Corazzari M, Fazi B, Donnorso RP, Pearson AD, Hall AG, Redfern CP, Piacentini M (2004) Gangliosides link the acidic sphingomyelinase-mediated induction of ceramide to 12-lipoxygenase-dependent apoptosis of neuroblastoma in response to fenretinide. J Natl Cancer Inst 96:1288–1299PubMedCrossRefGoogle Scholar
- 17.Puduvalli VK, Yung WK, Hess KR, Kuhn JG, Groves MD, Levin VA, Zwiebel J, Chang SM, Cloughesy TF, Junck L, Wen P, Lieberman F, Conrad CA, Gilbert MR, Meyers CA, Liu V, Mehta MP, Nicholas MK, Prados M (2004) Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: A North American Brain Tumor Consortium study. J Clin Oncol 22:4282–4289PubMedCrossRefGoogle Scholar
- 19.Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, Kao JC, Stenzel TT, Ahmed RBK, Tourt-Uhlig SE, Herndon JE2nd, Vredenburgh JJ, Sampson JH, Friedman AH, Bigner DD, Friedman HS (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:33–142Google Scholar
- 22.Shishodia S, Gutierrez AM, Lotan R, Aggarwal BB (2005) N-(4-hydroxyphenyl)retinamide inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of I(kappa)B(alpha) kinase and nuclear factor-kappaB-regulated gene products. Cancer Res 65:9555–9565PubMedCrossRefGoogle Scholar