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Research Articles

The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway

Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

Requests for reprints: Shi-Yong Sun, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road Northeast, C3088, Atlanta, GA 30322. Phone: 404-778-2170; Fax: 404-778-5520. E-mail: shi-yong.sun{at}emoryhealthcare.org

Abstract

The Akt inhibitor, perifosine, is an alkylphospholipid exhibiting antitumor properties and is currently in phase II clinical trials for various types of cancer. The mechanisms by which perifosine exerts its antitumor effects, including the induction of apoptosis, are not well understood. The current study focused on the effects of perifosine on the induction of apoptosis and its underlying mechanisms in human non–small cell lung cancer (NSCLC) cells. Perifosine, at clinically achievable concentration ranges of 10 to 15 µmol/L, effectively inhibited the growth and induced apoptosis of NSCLC cells. Perifosine inhibited Akt phosphorylation and reduced the levels of total Akt. Importantly, enforced activation of Akt attenuated perifosine-induced apoptosis. These results indicate that Akt inhibition is necessary for perifosine-induced apoptosis. Despite the activation of both caspase-8 and caspase-9, perifosine strikingly induced the expression of the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor, death receptor 5, and down-regulated cellular FLICE-inhibitory protein (c-FLIP), an endogenous inhibitor of the extrinsic apoptotic pathway, with limited modulatory effects on the expression of other genes including Bcl-2, Bcl-X_L, PUMA, and survivin. Silencing of either caspase-8 or death receptor 5 attenuated perifosine-induced apoptosis. Consistently, further down-regulation of c-FLIP expression with c-FLIP small interfering RNA sensitized cells to perifosine-induced apoptosis, whereas enforced overexpression of ectopic c-FLIP conferred resistance to perifosine. Collectively, these data indicate that activation of the extrinsic apoptotic pathway plays a critical role in perifosine-induced apoptosis. Moreover, perifosine cooperates with TRAIL to enhance the induction of apoptosis in human NSCLC cells, thus warranting future in vivo and clinical evaluation of perifosine in combination with TRAIL in the treatment of NSCLC. [Mol Cancer Ther 2007;6(7):2029–38]

Grant support: The Georgia Cancer Coalition Distinguished Cancer Scholar award (S-Y. Sun), Department of Defense grants W81XWH-04-1-0142-VITAL (S-Y. Sun for Project 4), DAMD17-01-1-0689-BESCT (F.R. Khuri), and an American Cancer Society Fellowship award (H.A. Elrod).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: H.A. Elrod and Y-D. Lin contributed equally to this work and share equal first authorship. F.R. Khuri and S-Y. Sun are Georgia Cancer Coalition Distinguished Cancer Scholars. H.A. Elrod is a recipient of an American Cancer Society Fellowship.

¹ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

² Unpublished data.

Received 1/ 4/07; revised 5/ 2/07; accepted 5/25/07.

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