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Abrogation of MAPK and Akt Signaling by AEE788 Synergistically Potentiates Histone Deacetylase Inhibitor-Induced Apoptosis through Reactive Oxygen Species Generation

Authors' Affiliations: Departments of ¹ Oncology and ² Molecular Pharmacology and ³ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; ⁴ Novartis Institutes for Biomedical Research, Boston, Massachusetts; and ⁵ Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Alex A. Adjei, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-4101; Fax: 716-845-3423; E-mail: alex.adjei{at}roswellpark.org.

Purpose: To evaluate the effects of combining the multiple receptor tyrosine kinase inhibitor AEE788 and histone deacetylase (HDAC) inhibitors on cytotoxicity in a broad spectrum of cancer cell lines, including cisplatin-resistant ovarian adenocarcinoma cells.

Experimental Design: Multiple cancer cell lines were treated in vitro using AEE788 and HDAC inhibitors (LBH589, LAQ824, and trichostatin A), either alone or in combination. Effects on cytotoxicity were determined by growth and morphologic assays. Effects of the combination on cell signaling pathways were determined by Western blotting, and the results were confirmed using pathway-specific inhibitors and transfection of constitutively active proteins.

Results: Cell treatment with AEE788 and HDAC inhibitors (LBH589, LAQ824, and trichostatin A) in combination resulted in synergistic induction of apoptosis in non–small cell lung cancer (MV522, A549), ovarian cancer (SKOV-3), and leukemia (K562, Jurkat, and ML-1) cells and in OV202hp cisplatin-resistant human ovarian cancer cells. AEE788 alone or in combination with LBH589 inactivated mitogen-activated protein kinase (MAPK) and Akt cascades. Inhibition of either MAPK and/or Akt enhanced LBH589-induced apoptosis. In contrast, constitutively active MAPK or Akt attenuated LBH589 or LBH589 + AEE788–induced apoptosis. Increased apoptosis was correlated with enhanced reactive oxygen species (ROS) generation. The free radical scavenger N-acetyl-L-cysteine not only substantially suppressed the ROS accumulation but also blocked the induction of apoptosis mediated by cotreatment with AEE788 and LBH589.

Conclusion: Collectively, these results show that MAPK and Akt inactivation along with ROS generation contribute to the synergistic cytotoxicity of the combination of AEE788 and HDAC inhibitors in a variety of human cancer cell types. This combination regimen warrants further preclinical and possible clinical study for a broad spectrum of cancers.