Downloads and Tools

•  Article PDF
  1.79 MB PDF document

XML File

•  Full Text XML
  119.57 KB XML Document

Supplemental Material

•  Supplemental File
  711.9 KB PDF document

This is an open access article.
Print this page Email this page

Recipient's Email:

---

Article Citation

RIS
MARC (XML)
FULL CITATION

---

Share on Facebook

Authors: Karolina Swiatek-Machado, Jakub Mieczkowski, Aleksandra Ellert-Miklaszewska, Piotr Swierk, Izabela Fokt, Slawomir Szymanski, Stanislaw Skora, Wiesław Szeja, Grzegorz Grynkiewicz, Bogdan Lesyng, Waldemar Priebe and Bozena Kaminska

Karolina Swiatek-Machado

Laboratory of Transcription Regulation; The Nencki Institute of Experimental Biology; Warsaw, Poland

Jakub Mieczkowski

Laboratory of Transcription Regulation; The Nencki Institute of Experimental Biology; Warsaw, Poland

Aleksandra Ellert-Miklaszewska

Laboratory of Transcription Regulation; The Nencki Institute of Experimental Biology; Warsaw, Poland

Piotr Swierk

Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology; Silesian University of Technology; Gliwice, Poland

Izabela Fokt

Department of Experimental Therapeutics; The University of Texas MD Anderson Cancer Center; Houston, TX USA

Slawomir Szymanski

Department of Experimental Therapeutics; The University of Texas MD Anderson Cancer Center; Houston, TX USA

Stanislaw Skora

Department of Experimental Therapeutics; The University of Texas MD Anderson Cancer Center; Houston, TX USA

Wiesław Szeja

Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology; Silesian University of Technology; Gliwice, Poland

Grzegorz Grynkiewicz

Pharmaceutical Research Institute; Warsaw, Poland

Bogdan Lesyng

Department of Biophysics and Center of Excellence BioExploratorium; Faculty of Physics; University of Warsaw; Warsaw, Poland; Bioinformatics Laboratory; Mossakowski Medical Research Center; Polish Academy of Sciences; Warsaw, Poland

Waldemar Priebe

Department of Experimental Therapeutics; The University of Texas MD Anderson Cancer Center; Houston, TX USA

Bozena Kaminska

Corresponding author: bozenakk@nencki.gov.pl
Laboratory of Transcription Regulation; The Nencki Institute of Experimental Biology; Warsaw, Poland

Abstract:
JAK (Janus kinase)/STAT (signal transducers and activators of transcription) signaling is involved in the regulation of cell growth, differentiation and apoptosis. Constitutive activation of STATs, in particular STAT3, is observed in a large number of human tumors, including gliomas and may contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis, thus it emerges as a promising target for anti-cancer therapy. To investigate the therapeutic potential of blocking STAT3 in glioma cells a set of small synthetic molecules - caffeic acid derivatives, structurally related to AG490 was screened for its ability to inhibit STAT3. Inhibitor 2 (E)-2-cyano-N-[(S)-1-phenylethyl]-3-(pyridin-2-yl)acrylamide was the most effective in inhibition of JAK/STAT3 signaling and at doses ≥ 25 μM significantly reduced the level of phosphorylated JAK1, JAK2 and STAT3 (at Tyr705) and downregulated the expression of known STAT3 targets. In treated cells we observed rapid detachment and rounding of cells associated with reduction of focal adhesion kinase phosphorylation and activity, followed by upregulation of phosphorylated p38, JNK and ERK1/2 levels. Accumulation of cells with fragmented DNA, increases of the cleaved caspase 3 and fragmented PARP levels were detected 24 h after the treatment suggesting ongoing apoptotic cell death. Three human malignant glioblastoma cell lines defective in tumor suppressors TP53 and/or PTEN were susceptible to inhibitor 2 that induced the programmed cell death. Global gene expression profiling revealed modulation of numerous genes in cells treated with inhibitor 2 revealing novel, potential JAK/STAT targets. Our study demonstrates that suitably modified caffeic acid molecules exhibit significant cytotoxic potential toward glioma cells.

Received: November 8, 2011; Accepted: March 20, 2012

Preview: