[Cancer Research 65, 2422-2432, March 15, 2005]
© 2005 American Association for Cancer Research
Experimental Therapeutics, Molecular Targets, and Chemical Biology |
Coadministration of Histone Deacetylase Inhibitors and Perifosine Synergistically Induces Apoptosis in Human Leukemia Cells through Akt and ERK1/2 Inactivation and the Generation of Ceramide and Reactive Oxygen Species
Mohamed Rahmani,
Erin Reese,
Yun Dai,
Cheryl Bauer,
Shawn G. Payne,
Paul Dent,
Sarah Spiegel and
Steven Grant
Departments of Medicine, Biochemistry, Pharmacology, and Radiation Oncology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
Requests for reprints: Steven Grant, Division of Hematology/Oncology, MCV Station, Box 230, Virginia Commonwealth University, Richmond, VA 23298. Phone: 804-828-5211; Fax: 804-828-8079; E-mail: stgrant{at}hsc.vcu.edu.
Interactions between histone deacetylase inhibitors (HDACIs) and the alkyl-lysophospholipid perifosine were examined in human leukemia cells. Coadministration of sodium butyrate, suberoylanilide hydroxamic acid (SAHA), or trichostatin with perifosine synergistically induced mitochondrial dysfunction (cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and a marked decrease in cell growth in U937 as well as HL-60 and Jurkat leukemia cells. These events were associated with inactivation of extracellular signal-regulated kinase (ERK) 1/2 and Akt, p46 c-jun-NH2-kinase (JNK) activation, and a pronounced increase in generation of ceramide and reactive oxygen species (ROS). They were also associated with up-regulation of Bak and a marked conformational change in Bax accompanied by membrane translocation. Ectopic expression of Bcl-2 delayed but was ultimately ineffective in preventing perifosine/HDACI-mediated apoptosis. Enforced expression of constitutively active mitogen-activated protein kinase kinase (MEK) 1 or myristoylated Akt blocked HDACI/perifosine-mediated ceramide production and cell death, suggesting that MEK/ERK and Akt inactivation play a primary role in these phenomena. However, inhibition of JNK activation (e.g., by the JNK inhibitor SP600125) did not attenuate sodium butyrate/perifosine-induced apoptosis. In addition, the free radical scavenger N-acetyl-L-cysteine attenuated ROS generation and apoptosis mediated by combined treatment. Finally, the acidic sphingomyelinase inhibitor desipramine attenuated HDACI/perifosine-mediated ceramide and ROS production as well as cell death. Together, these findings indicate that coadministration of HDACIs with perifosine in human leukemia cells leads to Akt and MEK/ERK disruption, a marked increase in ceramide and ROS production, and a striking increase in mitochondrial injury and apoptosis. They also raise the possibility that combining these agents may represent a novel antileukemic strategy.
Key Words: leukemia • perifosine • HDACIs • Akt • MEK/ERK • ceramide • apoptosis
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Copyright © 2005 by the American Association for Cancer Research.
