digitoxigenin and Lung-Neoplasms

Cardiac glycosides (CGs) are natural compounds traditionally used for the treatment of heart disorders, and recently new therapeutic possibilities were proposed. Their antitumor reports and clinical trials have notably enhanced, including those targeted for lung cancer, the most lethal type that lacks of new treatment agents, instigating the research of these molecules. The CGs studied here, named C10 {3β-[(N-(2-hydroxyethyl)aminoacetyl]amino-3-deoxydigitoxigenin} and C18 (3β-(aminoacetyl)amino-3-deoxydigitoxigenin), are semisynthetic derivatives prepared from digitoxigenin scaffold. Both compounds demonstrated high cytotoxicity for different cancer cell lines, especially H460 lung cancer cells, and their cytotoxic effects were deeply investigated using different methodological approaches. C10 induced cell death at lower concentrations and during shorter periods of treatment than C18, and increased the number of small and irregular nuclei, which are characteristics of apoptosis. This type of cell death was confirmed by caspase-3/7 assay. Both compounds reduced H460 cells proliferative potential by long-term action, and C10 showed the strongest potential. Moreover, these compounds induced a significant decrease of the area and viability of H460 spheroids providing preclinical favorable profiles to develop new chemotherapeutic agents.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Digitoxigenin; Humans; Lung Neoplasms; Tumor Cells, Cultured

Cardiac glycosides (CGs) are natural compounds widely used to treat several cardiac conditions and more recently have been recognized as potential antitumor agents. They are known as Na,K-ATPases ligands, which is a promising drug target in cancer. In this study, the short and long-lasting cytotoxic effects of the natural cardenolide digitoxigenin monodigitoxoside (DGX) were evaluated against two non-small cell lung cancer lines (A549 and H460 cells). It was found that DGX induced cytotoxic effects in both cells and the apoptotic effects were more pronounced on H460 cells. In long-term analysis, using the clonogenic and the cumulative population doubling (CPD) assays, DGX showed a reduction of cell survival, after 15days without re-treatment. To better understand DGX effects in A549 cells, several assays were conducted. In cell cycle analysis, DGX caused an arrest in S and G2/M phases. This compound also increased the number of cells in subG1 phase in a concentration- and time-dependent manner. The presence of β-galactosidase positive cells, large nucleus and flattened cells indicated senescence. Additionally, DGX inhibited Na,K-ATPase activity in A549 cells, as well as in purified pig kidney and in human red blood cell membrane preparations, at nanomolar range. Moreover, results of molecular docking showed that DGX binds with high efficiency (-11.4Kcal/mol) to the Na,K-ATPase (PDB:4HYT). Taken together, our results highlight the potent effects of DGX both in A549 and H460 cells, and disclose its link with Na,K-ATPase inhibition.

Topics: A549 Cells; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Survival; Digitoxigenin; Humans; Lung Neoplasms; Molecular Docking Simulation; Sodium-Potassium-Exchanging ATPase; Swine; Time Factors

Cardiac glycosides consist of a large family of naturally derived compounds that are clinically used to treat congestive heart failure, and also present anticancer properties. In this study, the cytotoxic effects of two cardenolides, digitoxigenin monodigitoxoside (DGX) and convallatoxin (CON) were screened in four human tumour cell lines. Both compounds showed anti-proliferative effects in all tumour cells, at nanomolar concentrations. Since the human lung cancer cell line A549 was the most sensitive, we investigated the anti-proliferative, anti-migratory and anti-invasive effects of these cardenolides. DGX and CON reduced A549 cell migration, being able to reduce more than 90% of cell invasion. Their effects on the expression of key regulators of metastatic mechanism showed decreased levels of MMP-2, MMP-9 and p-FAK. Both compounds also presented low toxicity for healthy cells. Finally, this work provides the first insights into the effects of these cardenolides on key steps of lung cancer metastasis.

Topics: A549 Cells; Cardenolides; Cardiac Glycosides; Cell Line, Tumor; Cell Movement; Cell Proliferation; Digitoxigenin; Humans; Lung Neoplasms; Neoplasm Metastasis; Strophanthins

In the present study, a 75% ethanol extract of Streptocaulon juventas (SJ), which had a strong inhibitory effect on the proliferation of human lung A549 adenocarcinoma cells, was subjected to bioassay-guided fractionation. The most active fraction (SJF) was obtained using a macroreticular resin column followed by a silica-gel column. Then its in vivo effect on lung cancer was investigated in athymic nude mice with A549 tumors while its effects on body weight, blood biochemical indicators, and organ indices were monitored. The results showed that SJF inhibited the tumor growth significantly at day 10 and day 15 during treatment without physical side effects. Following HPLC and NMR spectrometry, the main components of SJF were identified as digitoxigenin, periplogenin, and periplogenin glucoside.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apocynaceae; Cell Line, Tumor; Digitoxigenin; Lung Neoplasms; Mice; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Plant Extracts; Xenograft Model Antitumor Assays