Open Access

2-Triazenoazaindoles: Α novel class of triazenes inducing transcriptional down-regulation of EGFR and HER-2 in human pancreatic cancer cells

  • Authors:
    • Jan N. Kreutzer
    • Alessia Salvador
    • Patrizia Diana
    • Girolamo Cirrincione
    • Daniela Vedaldi
    • David W. Litchfield
    • Olaf-Georg Issinger
    • Barbara Guerra
  • View Affiliations

  • Published online on: November 29, 2011     https://doi.org/10.3892/ijo.2011.1272
  • Pages: 914-922
  • Copyright: © Kreutzer et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Pancreatic cancer is a complex malignancy arising from the accumulation of genetic and epigenetic defects in the affected cells. Standard chemotherapy for patients with advanced disease shows only modest effects and is associated with considerable toxicity. Overexpression or aberrant activation of members of the epidermal growth factor receptor tyrosine kinase family, which includes EGFR and HER-2, occurs frequently and is associated with multiple drug resistance and decreased patient survival. In this study, we have investigated the therapeutic potential of AS104, a novel compound of the triazene class, with potential inhibitory effects on EGFR. We found that treatment of cells with AS104 causes significant reduction of cell growth and metabolic activity in four human pancreatic cancer cell lines. Furthermore, we show that the AS104-mediated induction of apoptotic cell death is associated with stimulation of autophagy in a dose-dependent manner. Treatment of cells with AS104 results in significant down-regulation of EGFR and HER-2 expression and activity and subsequent inhibition of downstream signaling proteins. Quantitative RT-PCR analysis and assays with proteasome inhibitors revealed that AS104 regulates the expression of EGFR and HER-2 at the transcriptional level. These findings provide for the first time experimental evidence for efficacy of AS104 in the simultaneous transcriptional repression of EGFR and HER-2 genes and suggest that AS104 may have therapeutic potential in the treatment of pancreatic cancers that express high levels of the aforementioned receptor tyrosine kinases.
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April 2012
Volume 40 Issue 4

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Spandidos Publications style
Kreutzer JN, Salvador A, Diana P, Cirrincione G, Vedaldi D, Litchfield DW, Issinger O and Guerra B: 2-Triazenoazaindoles: Α novel class of triazenes inducing transcriptional down-regulation of EGFR and HER-2 in human pancreatic cancer cells. Int J Oncol 40: 914-922, 2012
APA
Kreutzer, J.N., Salvador, A., Diana, P., Cirrincione, G., Vedaldi, D., Litchfield, D.W. ... Guerra, B. (2012). 2-Triazenoazaindoles: Α novel class of triazenes inducing transcriptional down-regulation of EGFR and HER-2 in human pancreatic cancer cells. International Journal of Oncology, 40, 914-922. https://doi.org/10.3892/ijo.2011.1272
MLA
Kreutzer, J. N., Salvador, A., Diana, P., Cirrincione, G., Vedaldi, D., Litchfield, D. W., Issinger, O., Guerra, B."2-Triazenoazaindoles: Α novel class of triazenes inducing transcriptional down-regulation of EGFR and HER-2 in human pancreatic cancer cells". International Journal of Oncology 40.4 (2012): 914-922.
Chicago
Kreutzer, J. N., Salvador, A., Diana, P., Cirrincione, G., Vedaldi, D., Litchfield, D. W., Issinger, O., Guerra, B."2-Triazenoazaindoles: Α novel class of triazenes inducing transcriptional down-regulation of EGFR and HER-2 in human pancreatic cancer cells". International Journal of Oncology 40, no. 4 (2012): 914-922. https://doi.org/10.3892/ijo.2011.1272