Cardenolide-induced lysosomal membrane permeabilization demonstrates therapeutic benefits in experimental human non-small cell lung cancers.
Non-small cell lung cancers (NSCLCs) are the leading cause of cancer deaths in most developed countries. Targeting heat shock protein 70 (Hsp70) expression and function, together with the induction of lysosomal membrane permeabilization (LMP), could overcome the multiple anti-cell death mechanisms evidenced in NSCLCs that are responsible for the failure of currently used chemotherapeutic drugs. Because cardenolides bind to the sodium pump, they affect multiple signaling pathways and thus have a number of marked effects on tumor cell behavior. The aim of the present study was to characterize in vitro and in vivo the antitumor effects of a new cardenolide (UNBS1450) on experimental human NSCLCs. UNBS1450 is a potent source of in vivo antitumor activity in the case of paclitaxel-and oxaliplatin-resistant subcutaneous human NCI-H727 and orthotopic A549 xenografts in nude mice. In vitro UNBS1450-mediated antitumor activity results from the induction of nonapoptotic cell death. UNBS1450 mediates the decrease of Hsp70 at both mRNA and protein levels, and this is at least partly due to UNBS1450-induced downregulation of NFAT5/TonEBP (a factor responsible for the transcriptional control of Hsp70). These effects were paralleled by the induction of LMP, as evidenced by acridine orange staining and immunofluorescence analysis for cathepsin B accumulation.
Mijatovic
Tatjana
T
Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels, Brussels, Belgium.
Mathieu
Véronique
V
Gaussin
Jean-François
JF
De Nève
Nancy
N
Ribaucour
Fabrice
F
Van Quaquebeke
Eric
E
Dumont
Patrick
P
Darro
Francis
F
Kiss
Robert
R
D000165:Acridine Orange / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002298:Cardenolides / Q000494:pharmacology*; D002401:Cathepsin B / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008247:Lysosomes / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude
D000970:Antineoplastic Agents; D002298:Cardenolides; D018840:HSP70 Heat-Shock Proteins; C510008:UNBS 1450; D002401:Cathepsin B; D000165:Acridine Orange