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.