Cardiotonic steroids-mediated targeting of the Na(+)/K(+)-ATPase to combat chemoresistant cancers.
A large proportion of cancer patients fail to respond to conventional chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli and/or the acquisition of a multidrug resistant (MDR) phenotype during chronic chemotherapy. A new angle in chemotherapeutics against these cancer types associated with dismal prognoses would be the targeting of specific ion channels and pumps over expressed by cancer cells as compared to normal cells. Several reports suggest that the alpha subunits of the Na(+)/K(+)-ATPase (referred as sodium pump from now on) could be such targets, using cardiotonic steroids (CS) including cardenolides and bufadienolides. A significant proportion of non-small-cell-lung cancers (NSCLCs), glioblastomas (GBMs), melanomas and kidney cancers overexpresses the alpha-1 subunit of the sodium pump as compared to corresponding normal tissues, while colon cancers overexpress the alpha-3 subunit. Thus, a deeper knowledge of the structure-activity relationship (SAR), in terms of CS-mediated anticancer effects, to the sodium pump alpha subunits might enable the identification of potent anticancer agents with limited cardiotoxicity. The current review provides an in depth SAR analysis with respect to cardenolide- versus bufadienolide-mediated anticancer effects. Moreover, pharmacological data from in vitro and in vivo experiments, as well as pre-clinical and clinical trials regarding cardenolides to combat cancers associated with dismal prognoses are presented.
Laboratoire de Toxicologie-Faculté de Pharmacie, Université Libre de Bruxelles, Campus de la Plaine CP 205/01-Boulevard du Triomphe, 1050 Brussels, Belgium.
T
T
Mijatovic
F
F
Dufrasne
R
R
Kiss
D002301:Cardiac Glycosides / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects*; D013329:Structure-Activity Relationship
D002301:Cardiac Glycosides; D000254:Sodium-Potassium-Exchanging ATPase