Cytotoxic effects of the cardenolide convallatoxin and its Na,K-ATPase regulation

• Published in: Molecular and cellular biochemistry Vol. 428; no. 1-2; pp. 23 - 39
• Main Authors: Schneider, Naira Fernanda Zanchett, Silva, Izabella Thais, Persich, Lara, de Carvalho, Annelise, Rocha, Sayonarah C., Marostica, Lucas, Ramos, Ana Carolina Pacheco, Taranto, Alex G., Pádua, Rodrigo M., Kreis, Wolfgang, Barbosa, Leandro A., Braga, Fernão C., Simões, Cláudia M. O.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-04-2017; Springer; Springer Nature B.V
• Subjects: A549 Cells; Analysis; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; ATPases; Biochemistry; Biomedical and Life Sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cardiology; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Erythrocytes - drug effects; G2 Phase Cell Cycle Checkpoints - drug effects; Humans; Iodides; Kidney - drug effects; Kidney - enzymology; Life Sciences; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Medical Biochemistry; Molecular Docking Simulation; Non-small cell lung cancer; Oncology; Sodium-Potassium-Exchanging ATPase - chemistry; Sodium-Potassium-Exchanging ATPase - metabolism; Strophanthins - pharmacology; Swine; Cardenolides; Cytotoxic effects; Convallotoxin Convallatoxin; A549 cells; Na,K-ATPase; Apoptosis
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-016-2914-8

Cardenolides are cardiac glycosides, mostly obtained from natural sources. They are well known for their inhibitory action on the Na,K-ATPase, an effect that regulates cardiovascular alterations such as congestive heart failure and atrial arrhythmias. In recent years, they have also sparked new interest in their anticancer potential. In the present study, the cytotoxic effects of the natural cardenolide convallatoxin (CON) were evaluated on non-small cell lung cancer (A549 cells). It was found that CON induced cytostatic and cytotoxic effects in A549 cells, showing essentially apoptotic cell death, as detected by annexin V-propidium iodide double-staining, as well as changes in cell form. In addition, it prompted cell cycle arrest in G2/M and reduced cyclin B1 expression. This compound also increased the number of cells in subG1 in a concentration- and time-dependent manner. At a long term, the reduction of cumulative population doubling was shown along with an increase of
β
-galactosidase positive cells and larger nucleus, indicative of senescence. Subsequently, CON inhibited the Na,K-ATPase in A549 cells at nM concentrations. Interestingly, at the same concentrations, CON was unable to directly inhibit the Na,K-ATPase, either in pig kidney or in red blood cells. Additionally, results of docking calculations showed that CON binds with high efficiency to the Na,K-ATPase. Taken together, our data highlight the potent anticancer effects of CON in A549 cells, and their possible link with non-classical inhibition of Na,K-ATPase.