A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells

Molecular Cancer Therapeutics - Tập 6 Số 8 - Trang 2337-2345 - 2007
Arnold H. van der Luit1, Stefan R. Vink2, Jeffrey Klarenbeek1, Daniel Perrissoud3, Éric Solary4, Marcel Verheij1,5, Wim J. van Blitterswijk1
11Cellular Biochemistry and Divisions of
22Experimental Therapy,
34Zentaris GmbH, Frankfurt am Main, Germany; and
45Institut National de la Sante et de la Recherche Medicale U866/Université de Bourgogne, Laboratoire de Mort Cellulaire et Cancer, UFR de Médecine, Dijon, France
53Department of Radiotherapy, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, the Netherlands;

Tóm tắt

Abstract Single-chain alkylphospholipids, unlike conventional chemotherapeutic drugs, act on cell membranes to induce apoptosis in tumor cells. We tested four different alkylphospholipids, i.e., edelfosine, perifosine, erucylphosphocholine, and compound D-21805, as inducers of apoptosis in the mouse lymphoma cell line S49. We compared their mechanism of cellular entry and their potency to induce apoptosis through inhibition of de novo biosynthesis of phosphatidylcholine at the endoplasmic reticulum. Alkylphospholipid potency closely correlated with the degree of phosphatidylcholine synthesis inhibition in the order edelfosine > D-21805 > erucylphosphocholine > perifosine. In all cases, exogenous lysophosphatidylcholine, an alternative source for cellular phosphatidylcholine production, could partly rescue cells from alkylphospholipid-induced apoptosis, suggesting that phosphatidylcholine biosynthesis is a direct target for apoptosis induction. Cellular uptake of each alkylphospholipid was dependent on lipid rafts because pretreatment of cells with the raft-disrupting agents, methyl-β-cyclodextrin, filipin, or bacterial sphingomyelinase, reduced alkylphospholipid uptake and/or apoptosis induction and alleviated the inhibition of phosphatidylcholine synthesis. Uptake of all alkylphospholipids was inhibited by small interfering RNA (siRNA)–mediated blockage of sphingomyelin synthase (SMS1), which was previously shown to block raft-dependent endocytosis. Similar to edelfosine, perifosine accumulated in (isolated) lipid rafts independent on raft sphingomyelin content per se. However, perifosine was more susceptible than edelfosine to back-extraction by fatty acid-free serum albumin, suggesting a more peripheral location in the cell due to less effective internalization. Overall, our results suggest that lipid rafts are critical membrane portals for cellular entry of alkylphospholipids depending on SMS1 activity and, therefore, are potential targets for alkylphospholipid anticancer therapy. [Mol Cancer Ther 2007;6(8):2337–45]

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Molecular Cancer Therapeutics

Tập 6 Số 8

2337-2345

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