PURPOSE - Despite significant progress in cancer research many tumor entities still have an unfavorable prognosis. Activating Transcription Factor 5 (ATF5) is up-regulated in various malignancies and promotes apoptotic resistance.
We evaluated the efficacy and mechanisms of the first described synthetic cell-penetrating inhibitor of ATF5 function, CP-d/n-ATF5-S1.
EXPERIMENTAL DESIGN - Preclinical drug testing was performed in various treatment-resistant cancer cells and in vivo xenograft models.
RESULTS - CP-d/n-ATF5-S1 reduced the transcript levels of several known direct ATF5 targets. It depleted endogenous ATF5 and induced apoptosis across a broad panel of treatment refractory cancer cell lines, sparing non-neoplastic cells. CP-d/n-ATF5-S1 promoted tumor cell apoptotic susceptibility in part by reducing expression of the deubiquitinase Usp9X and lead to diminished levels of anti-apoptotic Bcl-2 family members Mcl-1 and Bcl-2. In line with this, CP-d/n-ATF5-S1 synergistically enhanced tumor cell apoptosis induced by the BH3-mimetic ABT263 and the death ligand TRAIL. In vivo, CP-d/n-ATF5-S1 attenuated tumor growth as a single compound in melanoma, glioblastoma, prostate cancer and triple-receptor-negative breast cancer xenograft models. Finally, the combination treatment of CP-d/n-ATF5-S1 and ABT263 significantly reduced tumor growth in vivo more efficiently than each reagent on its own.
CONCLUSIONS - Our data support the idea that CP-d/n-ATF5-S1, administered as a single reagent or in combination with other drugs, holds promise as an innovative, safe and efficient anti-neoplastic agent against treatment-resistant cancers.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Apr 28 [Epub ahead of print]
Georg Karpel-Massler, Basil A Horst, Chang Shu, Lily Chau, Takashi Tsujiuchi, Jeffrey N Bruce, Peter Canoll, Lloyd A Greene, James M Angelastro, Markus D Siegelin
Pathology and Cell Biology, Columbia University., Pathology and Cell Biology, Columbia University., Pathology and Cell Biology, Columbia University Medical Center., Pathology and Cell Biology, Columbia University Medical Center., Department of Neurosurgery, Columbia University., Department of Neurological Surgery, Columbia University., Pathology and Cell Biology, Columbia University., Pathology and Cell Biology, Columbia University Medical Center., Molecular Biosciences, UC Davis School of Veterinary Medicine., Pathology and Cell Biology, Columbia University Medical Center