Simultaneous gene silencing of KRAS and anti-apoptotic genes as a multitarget therapy
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Kristin Werner1, Franziska Lademann1, May-Linn Thepkaysone1, Beatrix Jahnke1, Daniela E. Aust2, Christoph Kahlert1, Georg Weber3, Jürgen Weitz1, Robert Grützmann3, Christian Pilarsky1
1Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany
2Institute of Pathology, TU Dresden, 01307 Dresden, Germany
3Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany
Christian Pilarsky, e-mail: email@example.com
Keywords: KRAS, apoptosis, RNAi, simultaneous gene silencing, pancreatic cancer
Received: June 30, 2015 Accepted: November 29, 2015 Published: December 26, 2015
Pancreatic cancer is one of the most lethal tumor types worldwide and an effective therapy is still elusive. Targeted therapy focused against a specific alteration is by definition unable to attack broad pathway signaling modification. Tumor heterogeneity will render targeted therapies ineffective based on the regrowth of cancer cell sub-clones. Therefore multimodal therapy strategies, targeting signaling pathways simultaneously should improve treatment.
SiRNAs against KRAS and the apoptosis associated genes BCLXL, FLIP, MCL1L, SURVIVIN and XIAP were transfected into human and murine pancreatic cancer cell lines. Induction of apoptosis was measured by Caspase 3/7 activation, subG1 FACS analysis and PARP cleavage. The therapeutic approach was tested in a subcutaneous allograft model with a murine cancer cell line.
By using siRNAs as a systematic approach to remodel signal transduction in pancreatic cancer the results showed increasing inhibition of proliferation and apoptosis induction in vitro and in vivo. Thus, siRNAs are suitable to model multimodal therapy against signaling pathways in pancreatic cancer. Improvements in in vivo delivery of siRNAs against a multitude of targets might therefore be a potential therapeutic approach.
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