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Received for publication February 9, 2005.
Revised May 20, 2005.
Accepted for publication May 20, 2005.
Kahalalide F (KF) is a novel marine-derived antitumor agent that is currently undergoing phase II clinical trials. The mechanism of action of KF is not well understood. In line with previous reports, we show that KF caused rapid and potent cytotoxicity in the breast cancer cell lines SKBR3 and BT474, characterized by cytoplasmic swelling and DNA clumping. Several markers of caspase-dependent apoptosis, such as phosphatidyl-serine externalization, cytochrome C release, and caspase-3 and PARP cleavage were negative after KF exposure. Inhibitors of caspases or cathepsins failed to protect against KF-cytotoxicity. Altogether, these data indicate that KF-induced cell death is a necrosis-like process. The sensitivity to KF in a panel of human tumor cell lines derived from breast (SKBR3, BT474, MCF7), vulval (A431), non-small cell lung (H460, A549, SW1573, H292), and hepatic (Skhep1, HepG2, Hep3B) carcinoma, positively correlated with ErbB3 (HER3) protein levels. A KF-resistant subline of colon carcinoma cells, HT29/KF, expressed significantly reduced levels of all ErbB receptors, but short term KF exposure of sensitive cell lines such as SKBR3 selectively induced downregulation of ErbB3. Conversely, stable transfection of an ErbB3-expressing plasmid increased the KF sensitivity of H460 cells, the most resistant cell line in our panel. Finally, we found that KF efficiently inhibited the PI3K-Akt signaling pathway in sensitive cell lines and that ectopic expression of a constitutively active Akt mutant reduced KF cytotoxicity in this cell line. In summary, our results identify ErbB3 and the downstream PI3K-Akt pathway as important determinants of the cytotoxic activity of KF in vitro.
Key words:
NGF/EGF, Protein Kinases (other), MAP Kinase, Apoptosis, Protein targets, Mechanisms of cell killing/apoptosis, Resistance
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