Combining TRAIL with PI3 kinase or HSP90 inhibitors enhances apoptosis in colorectal cancer cells via suppression of survival signaling
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Grazia Saturno1,3, Melanie Valenti1, Alexis De Haven Brandon1, George V. Thomas2,4, Suzanne Eccles1, Paul A. Clarke1, and Paul Workman1
1 Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
2 Divisions of Cancer Biology and Clinical Studies, The Institute of Cancer Research, London, UK.
3 Present address: Molecular Oncology Team, Paterson Institute for Cancer Research, The University of Manchester, Wilmslow Road, Manchester UK
4 Present address: HSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
Paul Workman, email:
Paul Clarke, email:
Keywords: TRAIL, PI3 Kinase/mTOR, HSP90, apoptosis, colorectal cancer
Received: July 9, 2013 Accepted: July 12, 2013 Published: July 14, 2013
TRAIL has been shown to induce apoptosis in cancer cells, but in some cases they fail to respond to this ligand. We explored the ability of representative phosphatidylinositol-3-kinase (PI3 Kinase)/mTOR and HSP90 inhibitors to overcome TRAIL resistance by increasing apoptosis in colorectal cancer models. We determined the sensitivity of 27 human colorectal cancer and 2 non-transformed colon epithelial cell lines to TRAIL treatment. A subset of the cancer cell lines with a range of responses to TRAIL was selected from the panel for treatment with TRAIL combined with the PI3 Kinase/mTOR inhibitor PI-103 or the HSP90 inhibitor 17-AAG (tanespimycin). Two TRAIL-resistant cell lines were selected for in vivo combination studies with TRAIL and 17-AAG. We found that 13 colorectal cancer cell lines and the 2 non-transformed colon epithelial cell lines were resistant to TRAIL. We demonstrated that co-treatment of TRAIL and PI-103 or 17-AAG was synergistic or additive and significantly enhanced apoptosis in colorectal cancer cells. This was associated with decreased expression or activity of survival protein biomarkers such as ERBB2, AKT, IKKα and XIAP. In contrast, the effect of the combination treatments in non-transformed colon cells was minimal. We show here for the first time that co-treatment in vivo with TRAIL and 17-AAG in two TRAIL-resistant human colorectal cancer xenograft models resulted in significantly greater tumor growth inhibition compared to single treatments. We propose that combining TRAIL with PI3 Kinase/mTOR or HSP90 inhibitors has therapeutic potential in the treatment of TRAIL-resistant colorectal cancers.
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