Na+/K+-ATPase alpha subunits as new targets in anticancer therapy.

BACKGROUND: The sodium pump (Na(+)/K(+)-ATPase) could be a target for the development of anticancer drugs as it serves as a signal transducer, it is a player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. Cardiotonic steroids (CS) are the natural ligands and inhibitors of the sodium pump and this supports the possibility of their development as anticancer agents targeting overexpressed Na(+)/K(+)-ATPase alpha subunits. OBJECTIVES: To highlight and further develop the concept of using Na(+)/K(+)-ATPase alpha1 and alpha3 subunits as targets in anticancer therapy and to address the question of the actual usefulness of further developing CS as anticancer agents. CONCLUSIONS: Targeting overexpressed Na(+)/K(+)-ATPase alpha subunits using novel CS might open a new era in anticancer therapy and bring the concept of personalized medicine from aspiration to reality. Clinical data are now needed to further support this proposal. Furthermore, future medicinal chemistry should optimize new anticancer CS to target Na(+)/K(+)-ATPase alpha subunits with the aim of rendering them more potent and less toxic.

Nucleolus and c-Myc: potential targets of cardenolide-mediated antitumor activity.

The use of cardenolides like ouabain, digitoxin, or oleandrin has been reported previously many times as a means of potentially combating human refractory prostate cancer by inducing apoptosis through an increase in intracellular calcium concentrations. The aims of the current study were to investigate if part of the antitumor effects mediated by cardenolides concerned disorganization of nucleolar structure and whether this was further associated with a marked decrease in c-Myc expression. Accordingly, the antitumor activity of a novel hemisynthetic cardenolide [1R,3aS,3bR,5aS,6aR,7aS,9R,12aR,13aR,15aR]-3a,11a-dihydroxy-13a-(hydroxymethyl)-9,15a-dimethyl-1-(5-oxo-2,5-dihydrofuran-3-yl)icosahydro-1H,4'H-spiro[cyclopenta [7,8]phenanthro[2,3-b]pyrano[3,2-e][1,4]dioxine-11,2'-[1,3]thiazolidin]-4'-one (UNBS1450)] was compared with that of classic cardenolides and reference anticancer agents in prostate cancer cell lines in vitro and in vivo following s.c. and orthotopic prostate cancer cell grafting into mice. The present study indicates that UNBS1450 markedly decreases the in vitro viability/proliferation of human prostate cancer cell lines but not of normal cells. The induced effects are not linked to an increase in intracellular calcium concentrations and subsequent induction of apoptosis. Rather, they appear to relate to the compound's capacity to disorganize nucleolar structure and function (through an impairment of cyclin-dependent kinase and c-Myc expression and related signaling pathways; paralleled by the disorganization of cancer cell-specific perinucleolar bodies as revealed by disruption of Sam68). This nonapoptotic cancer cell death mediated by severe nucleolar targeting and down-regulation of c-Myc expression is a completely new cardenolide-induced mechanism of antitumor action.

Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas.

The therapeutic goal of cancer treatment has been to trigger tumor-selective cell death. Although cell death can be achieved not only by apoptosis (type I programmed cell death) but also by necrosis, mitotic catastrophe, and autophagy, drugs inducing apoptosis remain the main chemotherapeutic agents in medical oncology. However, cancer cells in their relentless drive to survive, hijack cell processes, resulting in apoptosis resistance, which underlies not only tumorigenesis but also the inherent resistance of certain cancers to radiotherapy and chemotherapy. Unlike apoptosis, which is a caspase-dependent process characterized by nuclear condensation and fragmentation, autophagic cell death is a caspase-independent process characterized by the accumulation of autophagic vacuoles in the cytoplasm accompanied by extensive degradation of the Golgi apparatus, the polyribosomes, and the endoplasmic reticulum, which precedes the destruction of the nucleus. The most striking evidence for proautophagic chemotherapy to overcome apoptosis resistance in cancer cells comes from the use of temozolomide, a proautophagic cytotoxic drug, which has demonstrated real therapeutic benefits in glioblastoma patients and is in clinical trials for several types of apoptosis-resistant cancers. A number of potential common targets in autophagy and apoptosis resistance pathways, that is, mammalian target of rapamycin (mTOR), phosphatidylinositol 3' kinase (PI3K), and Akt have been identified. Thus, further success in certain devastating cancers might be achieved by the combination of proautophagic drugs such as temozolomide with mTOR, PI3K, or Akt inhibitors, or with endoplasmic reticulum stress inhibitors as adjuvant chemotherapies.