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Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinaseAkt/PKB survival pathway

Ruiter, Gerald A.a b; Zerp, Shuraila F.a b; Bartelink, Harrya; van Blitterswijk, Wim J.b; Verheij, Marcela b

Preclinical Reports

Synthetic alkyl-lysophospholipids (ALPs) represent a new class of anti-tumor agents that target cell membranes and induce apoptosis. However, the exact mechanisms by which ALPs exert these effects remain unclear. Here, we investigated in the epithelial carcinoma cell lines A431 and HeLa the effect of three clinically relevant ALPs [Et-18-OCH3 (Edelfosine), HePC (Miltefosine) and D-21266 (Perifosine)] on the phosphatidylinositol 3-kinase (PI3K)–Akt/PKB survival pathway. We found that growth factor-induced Akt/PKB activation in these cells is dependent on PI3K and that all three ALPs inhibited this pathway in a dose-dependent manner. We further showed that inhibition of the PI3K–Akt/PKB pathway by wortmannin or ALPs is associated with activation of the pro-apoptotic SAPK/JNK pathway. Inhibition of the PI3K–Akt/PKB survival pathway represents a novel mode of action of ALPs that may significantly contribute to the induction of apoptosis.

aDepartment of Radiotherapy

bDivision of Cellular Biochemistry, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands

Correspondence to M. Verheij, Department of Radiotherapy, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Tel: +31 20 512 2124; fax: +31 20 669 1101;

e-mail: m.verheij@nki.nl

Received 18 October 2002 Accepted 19 November 2002

© 2003 Lippincott Williams & Wilkins, Inc.