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¹ Laboratory of Toxicology, Institute of Pharmacy, ² Laboratory of Virology, Faculty of Medicine, Free University of Brussels; and ³ Unibioscreen S.A., Brussels, Belgium

Requests for reprints: Robert Kiss, Laboratory of Toxicology, Institute of Pharmacy (CP 205/1), Université Libre de Bruxelles, Campus Plaine, Boulevard du Triomphe, 1050 Brussels, Belgium. Phone: 32-47762-2083; Fax: 32-2332-5335. E-mail: rkiss{at}ulb.ac.be

Non–small cell lung cancers (NSCLC) are associated with very dismal prognoses, and adjuvant chemotherapy, including irinotecan, taxanes, platin, and Vinca alkaloid derivatives, offers patients only slight clinical benefits. Part of the chemoresistance of NSCLCs results from the constitutive or anticancer drug-induced activation of the nuclear factor-B (NF-B) signaling pathways. The present study shows that human A549 NSCLC cells display highly activated cytoprotective NF-B signaling pathways. UNBS1450, which is a cardenolide belonging to the same class of chemicals as ouabain and digitoxin, affected the expression and activation status of different constituents of the NF-B pathways in these A549 tumor cells. The modifications brought about by UNBS1450 led to a decrease in both the DNA-binding capacity of the p65 subunit and the NF-B transcriptional activity. Using the 3-(4,5-dimethylthiazol-2yl)-dephenyltetrazolium bromide colorimetric assay, we observed in vitro that UNBS1450 was as potent as taxol and SN38 (the active metabolite of irinotecan) in reducing the overall growth levels of the human A549 NSCLC cell line, and was more efficient than platin derivatives, including cisplatin, carboplatin, and oxaliplatin. The chronic in vivo i.p. and p.o. UNBS1450 treatments of human A549 orthotopic xenografts metastasizing to the brains and the livers of immunodeficient mice had a number of significant therapeutic effects on this very aggressive model. [Mol Cancer Ther 2006;5(2):391–9]

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Received 9/13/05; revised 10/31/05; accepted 12/ 1/05.