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

Pancreatic cancer is a complex malignancy arising from the accumulationof genetic and epigenetic defects in the affected cells. Standard chemotherapyfor patients with advanced disease shows only modest effects and is associatedwith considerable toxicity. Overexpression or aberrant activation of members ofthe epidermal growth factor receptor tyrosine kinase family, which includes EGFRand HER-2, occurs frequently and is associated with multiple drug resistance anddecreased patient survival. In this study, we have investigated the therapeuticpotential of AS104, a novel compound of the triazene class, with potential inhibitoryeffects on EGFR. We found that treatment of cells with AS104 causes significantreduction of cell growth and metabolic activity in four human pancreatic cancercell lines. Furthermore, we show that the AS104-mediated induction of apoptoticcell death is associated with stimulation of autophagy in a dose-dependent manner.Treatment of cells with AS104 results in significant down-regulation of EGFR andHER-2 expression and activity and subsequent inhibition of downstream signalingproteins. Quantitative RT-PCR analysis and assays with proteasome inhibitors revealedthat AS104 regulates the expression of EGFR and HER-2 at the transcriptional level.These findings provide for the first time experimental evidence for efficacy ofAS104 in the simultaneous transcriptional repression of EGFR and HER-2 genes andsuggest that AS104 may have therapeutic potential in the treatment of pancreaticcancers that express high levels of the aforementioned receptor tyrosine kinases.