Cytotoxic effects of the cardenolide convallatoxin and its Na,K-ATPase regulation.
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.
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina (UFSC), LVA, CIF, CCS, Florianópolis,, SC, 88040-900, Brazil.
Naira Fernanda Zanchett
NFZ
Schneider
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina (UFSC), LVA, CIF, CCS, Florianópolis,, SC, 88040-900, Brazil.
Izabella Thais
IT
Silva
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina (UFSC), LVA, CIF, CCS, Florianópolis,, SC, 88040-900, Brazil.
Lara
L
Persich
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina (UFSC), LVA, CIF, CCS, Florianópolis,, SC, 88040-900, Brazil.
Annelise
A
de Carvalho
Laboratório de Bioquímica Celular, Campus Centro-Oeste Dona Lindu, Universidade Federal de São João del Rei, Divinopolis, MG, Brazil.
Sayonarah C
SC
Rocha
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina (UFSC), LVA, CIF, CCS, Florianópolis,, SC, 88040-900, Brazil.
Lucas
L
Marostica
Laboratório de Bioquímica Celular, Campus Centro-Oeste Dona Lindu, Universidade Federal de São João del Rei, Divinopolis, MG, Brazil.
Ana Carolina Pacheco
ACP
Ramos
Laboratório de Bioinformática, Campus Centro Oeste Dona Lindu, Universidade Federal de São João Del Rei, Divinópolis, MG, Brazil.
Alex G
AG
Taranto
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Rodrigo M
RM
Pádua
Department of Biology, Friedrich-Alexander Universität, Erlangen, Germany.
Wolfgang
W
Kreis
Laboratório de Bioquímica Celular, Campus Centro-Oeste Dona Lindu, Universidade Federal de São João del Rei, Divinopolis, MG, Brazil.
Leandro A
LA
Barbosa
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Fernão C
FC
Braga
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina (UFSC), LVA, CIF, CCS, Florianópolis,, SC, 88040-900, Brazil. claudia.simoes@ufsc.br.
Cláudia M O
CMO
Simões
D000072283:A549 Cells; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D062105:Molecular Docking Simulation; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000378:metabolism*; D013328:Strophanthins / Q000494:pharmacology*; D013552:Swine
D000972:Antineoplastic Agents, Phytogenic; D013328:Strophanthins; D000254:Sodium-Potassium-Exchanging ATPase; C000505:convallatoxin
A549 cells; Apoptosis; Cardenolides; Convallotoxin Convallatoxin; Cytotoxic effects; Na,K-ATPase