Cancer cell mitochondria targeted by marine antitumor drug lamellarin D
Released : May 17, 2006 7:05 AM
2006 MAY 17 - (NewsRx.com) -- Cancer cell mitochondria could be targeted by marine antitumor drug lamellarin D.
According to a study from France, "Lamellarin D is a marine alkaloid with a pronounced cytotoxicity against a large panel of cancer cell lines and is a potent inhibitor of topoisomerase I. However, lamellarin D maintains a marked cytotoxicity toward cell lines resistant to the reference topoisomerase I poison camptothecin. We therefore hypothesized that topoisomerase I is not the only cellular target for the drug."
"Using complementary cell-based assays, we provide evidence that lamellarin D acts on cancer cell mitochondria to induce apoptosis," explained J. Kluza and colleagues, INSERM U459. "Lamellarin D, unlike camptothecin, induces early disruption of the inner mitochondrial transmembrane potential (Delta psi(m) in the P388 leukemia cell line. The functional alterations are largely prevented by cyclosporin A, an inhibitor of the mitochondrial permeability transition (MPT), but not by the inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone.
"Delta psi(m) disruption is associated with mitochondrial swelling and cytochrome c leakage. Using a reliable real-time flow cytometric monitoring of Delta psi(m), and swelling of mitochondria isolated from leukemia cells, we show that lamellarin D has a direct NIPT-inducing effect. Furthermore, mitochondria are required in a cell-free system to mediate lamellarin D-induced nuclear apoptosis.
"The direct mitochondrial effect of lamellarin D accounts for the sensitivity of topoisomerase I-mutated P388CPT5 cells resistant to camptothecin. Interestingly, a tumor-active analogue of lamellarin D, designated PM031379, also exerts a direct proapoptotic action on mitochondria, with a more pronounced activity toward mitochondria of tumor cell lines compared with nontumor cell lines," stated the investigators.
The researchers concluded, "Altogether, this work reinforces the pharmacologic interest of the lamellarins and defines lamellarin D as a lead in the search for treatments against chemoresistant cancer cells."
Kluza and colleagues published the results of their research in Cancer Research (Cancer cell mitochondria are direct proapoptotic targets for the marine antitumor drug lamellarin D. Cancer Res, 2006;66(6):3177-3187).
For additional information, contact P. Marchetti, INSERM, U459, 1 Pl Verdun, F-59045 Lille, France.
The publisher of the journal Cancer Research can be contacted at: American Association Cancer Research, 615 Chestnut St., 17th Floor, Philadelphia, PA 19106-4404, USA.
Keywords: Lille, France, Apoptosis, Camptothecin, Cyclosporin, Cyclosporin A, Enzymes, Enzymology, Leukemia, Oncology, Proteins, Proteomics, Cancer Therapy, Topoisomerase I, Tumors, Chemotherapy, Lamellarin D, Camptothecin, Chemoresistance.
This article was prepared by Vaccine Weekly editors from staff and other reports. Copyright 2006, Vaccine Weekly via NewsRx.com.
Copyright 2006 Vaccine Weekly via NewsRx.com