Apoptosis in human liver carcinoma caused by gold nanoparticles in combination with carvedilol is mediated via modulation of MAPK/Akt/mTOR pathway and EGFR/FAAD proteins

  • Authors:
    • Raimundo F. De Araújo Jr
    • Jonas B. Pessoa
    • Luis J. Cruz
    • Alan B. Chan
    • Emílio De Castro Miguel
    • Rômulo S. Cavalcante
    • Gerly Anne C. Brito
    • Heloiza Fernada O. Silva
    • Luiz H.S. Gasparotto
    • Paulo M.M. Guedes
    • Aurigena A. Araújo
  • View Affiliations

  • Published online on: October 27, 2017     https://doi.org/10.3892/ijo.2017.4179
  • Pages:189-200
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Abstract

In cancers, apoptosis signaling pathways and cell survival and growth pathways responsible for resistance to conventional treatments, such as Pi3K/Akt/mTOR and mitogen-activated protein kinase (MAPK) become dysregulated. Recently, alternative treatments to promote tumor cell death have become important. The present study reports on the antitumor and cytoprotective action of gold nanoparticles (GNPs) and carvedilol in combination and in isolated application. Apoptosis was analyzed by FITC/propidium iodide staining flow cytometry; caspase-3, caspase-8, Bcl-2 and MAPK/ERK activity by immunofluorescence microscopy; gene expression of proteins related to cell death as Akt, mTOR, EGFR, MDR1, survivin, FADD and Apaf, by the real-time PCR; and western blot analysis for MAPK/ERK, Akt and mTOR. Oxidative stress evaluation was performed by reduced glutathione (GSH) and malondialdehyde (MDA) levels. Intracellular GNPs targets were identified by transmission electron microscopy. After exposure to a combination of GNPs (6.25 µg/ml) and carvedilol (3 µM), death as promoted by apoptosis was detected using flow cytometry, for expression of pro-apoptotic proteins FADD, caspase-3, caspase-8 and sub-regulation of anti-apoptotic MAPK/ERK, Akt, mTOR, EGFR and MDR1 resistance. Non-tumor cell cytoprotection with GSH elevation and MDA reduction levels was detected. GNPs were identified within the cell near to the nucleus when combined with carvedilol. The combination of GNP and carvedilol promoted downregulation of anti-apoptotic and drug resistance genes, over-regulation of pro-apoptotic proteins in tumor cells, as well as cytoprotection of non-tumor cells with reduction of apoptosis and oxidative stress.

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January 2018
Volume 52 Issue 1

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

2016 Impact Factor: 3.079
Ranked #33/217 Oncology
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APA
De Araújo Jr, R.F., Pessoa, J.B., Cruz, L.J., Chan, A.B., De Castro Miguel, E., Cavalcante, R.S. ... Araújo, A.A. (2018). Apoptosis in human liver carcinoma caused by gold nanoparticles in combination with carvedilol is mediated via modulation of MAPK/Akt/mTOR pathway and EGFR/FAAD proteins. International Journal of Oncology, 52, 189-200. https://doi.org/10.3892/ijo.2017.4179
MLA
De Araújo Jr, R. F., Pessoa, J. B., Cruz, L. J., Chan, A. B., De Castro Miguel, E., Cavalcante, R. S., Brito, G. C., Silva, H. O., Gasparotto, L. H., Guedes, P. M., Araújo, A. A."Apoptosis in human liver carcinoma caused by gold nanoparticles in combination with carvedilol is mediated via modulation of MAPK/Akt/mTOR pathway and EGFR/FAAD proteins". International Journal of Oncology 52.1 (2018): 189-200.
Chicago
De Araújo Jr, R. F., Pessoa, J. B., Cruz, L. J., Chan, A. B., De Castro Miguel, E., Cavalcante, R. S., Brito, G. C., Silva, H. O., Gasparotto, L. H., Guedes, P. M., Araújo, A. A."Apoptosis in human liver carcinoma caused by gold nanoparticles in combination with carvedilol is mediated via modulation of MAPK/Akt/mTOR pathway and EGFR/FAAD proteins". International Journal of Oncology 52, no. 1 (2018): 189-200. https://doi.org/10.3892/ijo.2017.4179