digitoxin and Neoplasms

Drug repositioning is a successful approach in medicinal research. It significantly simplifies the long-term process of clinical drug evaluation, since the drug being tested has already been approved for another condition. One example of drug repositioning involves cardiac glycosides (CGs), which have, for a long time, been used in heart medicine. Moreover, it has been known for decades that CGs also have great potential in cancer treatment and, thus, many clinical trials now evaluate their anticancer potential. Interestingly, heart failure and cancer are not the only conditions for which CGs could be effectively used. In recent years, the antiviral potential of CGs has been extensively studied, and with the ongoing SARS-CoV-2 pandemic, this interest in CGs has increased even more. Therefore, here, we present CGs as potent and promising antiviral compounds, which can interfere with almost any steps of the viral life cycle, except for the viral attachment to a host cell. In this review article, we summarize the reported data on this hot topic and discuss the mechanisms of antiviral action of CGs, with reference to the particular viral life cycle phase they interfere with.

Topics: Antiviral Agents; Cardiac Glycosides; COVID-19; Digitoxin; Digoxin; Drug Repositioning; Heart Failure; Humans; Neoplasms; Ouabain; Pandemics; SARS-CoV-2; Sodium-Potassium-Exchanging ATPase; Virus Internalization; Virus Replication

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

The clinical benefit of digitalis for patients with heart disease is well established. However, recent studies have also suggested that digitalis has antineoplastic activities at clinically relevant serum concentrations. Much of the early evidence supporting the anticancer activity of digitalis has been circumstantial. Observational studies suggest a protective benefit and improved outcomes in patients who develop cancer while they are taking digitalis. The mechanism by which digitalis selectively affects the growth of malignant cells is complex, involving several important signaling pathways. Experiments to determine its mechanism of action have demonstrated that digitalis inhibits cell growth and angiogenesis and induces apoptosis in multiple cancer cell lines. Most, if not all, of these effects are mediated through its target enzyme, sodium- and potassium-activated adenosine triphosphatase. This article reviews the literature, which supports the use of digitalis in patients with malignancies with a discussion of the potential mechanisms of action. We hypothesize that sodium- and potassium-activated adenosine triphosphatase is an important new target for cancer therapy. It is reasonable to expect that the addition of digitalis to current cancer treatments will improve the clinical outcomes.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Digitalis; Digitalis Glycosides; Drug Design; Drug Resistance, Neoplasm; Humans; Medical Oncology; Neoplasms; Neovascularization, Pathologic; Plant Extracts; Signal Transduction; src-Family Kinases; Treatment Outcome

Accumulating preclinical and clinical data suggest that the cardiac drug digitoxin might be used in cancer therapy. Recent reports have shown that digitoxin can inhibit the growth and induce apoptosis in cancer cells at concentrations commonly found in the plasma of cardiac patients treated with this drug. Several mechanisms have been associated with the anticancer activity of digitoxin, yet at present it is unknown why malignant cells are more susceptible to this cardiac glycoside than non-malignant cells. This report analyses the possible anticancer mechanisms of digitoxin and proposes that the inhibition of glycolysis may be a key mechanism by which this natural product selectively targets cancer cells. Finally, whether or not there is enough evidence to support the clinical evaluation of digitoxin in patients with cancer is discussed.

Topics: Animals; Antineoplastic Agents; Digitoxin; Glycolysis; Humans; Neoplasms; Tumor Cells, Cultured

The primary transport system of sodium and potassium across the plasma cell membrane, the Na/K-ATPase, is a vital enzyme involved in numerous cellular events. This enzyme is the receptor for plant and amphibian steroids such as ouabain, digoxin and bufalin. In the past decade several endogenous steroids, identical or similar to the plant and amphibian steroids, termed here collectively digitalis-like compounds (DLC), have been identified in human tissues. This paper raises the hypothesis that alterations in the metabolism of endogenous DLC and in their interactions with the Na/K-ATPase may be associated with the development of malignancies. This hypothesis is based on the review of the literature pointing to: 1. An abnormal activity of the Na/K-ATPase and its sensitivity to DLC in malignant cells; 2. Abnormal plasma DLC concentrations in cancer patients; 3. Abnormal synthesis and release of DLC in immune compromised mice; and 4. Beneficial effects of DLC in the treatment of cancer.

Topics: Animals; Cardenolides; Digitalis; Humans; Neoplasms; Saponins; Sodium-Potassium-Exchanging ATPase

One of the most complex challenges to the toxicologist represents extrapolation from laboratory animals to humans. In this article, we review interspecies differences in metabolism and toxicity of heterocyclic amines, aflatoxin B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and related compounds, endocrine disrupters, polycyclic aromatic hydrocarbons, tamoxifen, and digitoxin. As far as possible, extrapolations to human toxicity and carcinogenicity are performed. Humans may be more susceptible to the carcinogenic effect of heterocyclic amines than monkeys, rats, and mice. Especially, individuals with high CYP1A2 and 3A4 activities and the rapid acetylator phenotype may be expected to have an increased risk. Striking interspecies variation in susceptibility to aflatoxin B1 carcinogenesis is known, with rats representing the most sensitive and mice the most resistant species, refractory to dietary levels three orders of magnitude higher than rats. An efficient conjugation with glutathione, catalyzed by glutathione S-transferase mYc, confers aflatoxin B1 resistance to mice. Extremely large interspecies differences in TCDD-induced toxicity are known. The guinea pig is the most susceptible mammal known, with an LD50 in the range 1-2 micrograms TCDD/kg, whereas the hamster is the most resistant species with an LD50 greater than 3000 micrograms/kg. A number of experts have pointed out to the fact that humans appear to be less sensitive to TCDD than most laboratory animals. Human exposure to background levels of TCDD is not likely to cause an incremental cancer risk. A clear cause--effect relationship has been shown between environmental endocrine-disrupting contaminants and adverse health effects in wildlife, whereas the effects seem to be less critical for humans. Studies on DNA adduct formation and metabolism of the nonsteroidal antiestrogen tamoxifen indicate that rats and mice are orders of magnitude more susceptible than humans.

Topics: Aflatoxin B1; Animals; Antineoplastic Agents, Hormonal; Benzo(a)pyrene; Cardiotonic Agents; Cricetinae; Digitoxin; Disease Susceptibility; Endocrine System; Estrogens; Female; Heterocyclic Compounds; Humans; Male; Mice; Microsomes, Liver; Neoplasms; Polychlorinated Dibenzodioxins; Rabbits; Rats; Species Specificity; Tamoxifen

Colon cancer patients with mutant KRAS are resistant to cetuximab, an antibody directed against the epidermal growth factor receptor. New treatment options are needed to improve survival in patients with KRAS mutated colorectal cancer. Digitoxin is a cardiotonic drug, which has been demonstrated to exhibit anticancer effects in a number of cancers. However, the anticancer mechanisms of digitoxin in KRAS mutant human colon cancer cells remain elusive. Our result demonstrated that digitoxin but not cetuximab markedly decreased the expression of hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription 3 (STAT3) and p-STAT3 protein in KRAS mutant colon cancer cells. Further analysis revealed that digitoxin inhibited HIF-1α protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-1α protein. The phosphorylation levels of ribosomal protein S6 kinase (p70S6K) and eIF4E binding protein-1 (4E-BP1) were significantly suppressed by digitoxin. Digitoxin inhibited the expression and activation of STAT3 through upregulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN), SHP1 and protein inhibitors of activated STAT3 (PIAS3) and direct binding to STAT3. Meanwhile, digitoxin inhibited HIF-1α in STAT3-independent manner in KRAS mutant colon cancer cells. Moreover, digitoxin promoted apoptosis and inhibited proliferation and migration, which was potentially mediated by suppression of HIF-1α and STAT3. We also found that digitoxin administration inhibited tumor growth in a mouse xenograft model. Taken together, our findings highlight the therapeutic potential of digitoxin for the treatment of cetuximab-resistant human colon cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Digitoxin; Down-Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mutation; Neoplasms; Proto-Oncogene Proteins p21(ras); Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Sweet'n low in stereo: A Wharton reaction was employed along with a diastereoselective palladium-catalyzed glycosylation and other post-glycosylation transformations to synthesize digitoxin analogues. Cytotoxic evaluation against a panel of cancer cell lines uncovered the stereochemical and substitutional limits of the C3'/C4'-hydroxy functionality in digitoxin monosaccharide.

Topics: Antineoplastic Agents; Cardiotonic Agents; Catalysis; Cell Line, Tumor; Digitoxigenin; Digitoxin; Drug Screening Assays, Antitumor; Glycosylation; Humans; Neoplasms; Palladium; Stereoisomerism

Two new compounds, a furostanol glycoside (1) and a pregnane glycoside (4), along with eight known compounds, belonging to the classes of spirostane (2,3), pregnane (5-7) and cardenolide (8-10) glycosides, were isolated from the seeds of Digitalis ciliata. Their structures were elucidated by 1D and 2D-NMR experiments as well as ESI-MS analysis. For the first time pregnane glycosides of the diginigenin series have been isolated from D. ciliata. The cytotoxic effects of compounds 1-10 on cell viability of several cancer cell lines, namely human breast cancer (MCF-7), human glioblastoma (T98G), human lung adenocarcinoma (A549), human colon carcinoma (HT-29), and human prostate cancer (PC-3) cell lines were evaluated. Compounds 1, 4, 7 and 8 showed antiproliferative effects against MCF-7, HT-29 and A549 cancer cells with IC₅₀ values ranging from 8.3 to 20 μM. The effects of compounds 1-10 on cell proliferation were evaluated on these three cancer cell lines by cell cycle analysis of DNA content using flow cytometry. Compounds 7, 8 and 10 induced significant changes in G₂/M cell cycle phase of all analyzed cells. The obtained results indicate that compounds 7, 8 and 10 are cytostatic compounds effective in reducing cell proliferation by inducing accumulation of the cells in the G₂/M phase of the cell cycle.

Topics: Antineoplastic Agents, Phytogenic; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Digitalis; DNA; Female; Glycosides; HT29 Cells; Humans; Male; Molecular Structure; Neoplasms; Phytotherapy; Plant Extracts; Pregnanes; Seeds; Steroids; Sterols

In phytotherapy, extracts from medicinal plants are employed which contain mixtures of secondary metabolites. Their modes of action are complex because the secondary metabolites can react with single or multiple targets. The components in a mixture can exert additive or even synergistic activities. In this study, the cytotoxicity of some phytochemicals, including phenolics (EGCG and thymol), terpenoids (menthol, aromadendrene, β-sitosterol-O-glucoside, and β-carotene) and alkaloids (glaucine, harmine, and sanguinarine) were investigated alone or in combination with the cytotoxic monodesmosidic steroidal saponin digitonin in Caco-2, MCF-7, CEM/ADR5000, and CCRF-CEM cells. Digitonin was combined in non-toxic concentrations (5μM in each cell line; except in MCF-7 the concentration was 2μM), together with a selection of phenolics, terpenoids, and alkaloids to evaluate potential synergistic or additive effects. An enhanced cytotoxicity was observed in most combinations. Even multi-drug resistant (MDR) cells (such as CEM/ADR5000 cells), with a high expression of P-glycoprotein, were responsive to combinations. Sanguinarine was the most cytotoxic alkaloid against CEM/ADR5000, MCF-7, and CCRF-CEM cells alone and in combination with digitonin. As compared to sanguinarine alone, the combination was 44.53-, 15.38-, and 6.65-fold more toxic in each cell line, respectively. Most combinations synergistically increased the cytotoxicity, stressing the importance of synergy when using multi-target drugs and mixtures in phytotherapy.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzophenanthridines; Caco-2 Cells; Digitalis; Digitonin; Drug Resistance, Multiple; Drug Synergism; Female; Humans; Isoquinolines; MCF-7 Cells; Neoplasms; Phenols; Phytotherapy; Plant Extracts; Terpenes

The article provides a mathematical description based on the theory of differential equations, for the proliferation of malignant cells (cancer). A model is developed which enables us to describe and predict the dynamics of cell proliferation much better than by using ordinary curve fitting procedures. By using differential equations the ability to foresee the dynamics of cell proliferation is in general much better than by using polynomial extrapolations. Complex time relations can be revealed. The mass of each living cell and the number of living cells are described as functions of time, accounting for each living cell's age since cell-birth. The linkage between micro-dynamics and the population dynamics is furnished by coupling the mass increase of each living cell up against the mitosis rate. A comparison is made by in vitro experiments with cancer cells exposed to digitoxin, a new promising anti-cancer drug. Theoretical results for the total number of cells (living or dead) is found to be in good agreement with experiments for the cell line considered, assuming different concentrations of digitoxin. It is shown that for the chosen cell line, the proliferation is halted by an increased time from birth to mitosis of the cells. The delay is probably connected with changes in the Ca concentration inside the cell. The enhanced time between the birth and mitosis of a cell leads effectively to smaller mitosis rates and thereby smaller proliferation rates. This mechanism is different from the earlier results on digitoxin for different cell lines where an increased rate of apoptosis was reported. But we find it reasonable that cell lines can react differently to digitoxin. A development from enhanced time between birth and mitosis to apoptosis can be furnished, dependent of the sensitivity of the cell lines. This mechanism is in general very different from the mechanism appealed to by standard chemotherapy and radiotherapy where the death ratios of the cells are mainly affected. Thus the analysis supports the view that a quite different mechanism is invoked when using digitoxin. This is important, since by appealing to different types of mechanism in parallel during cancer treatment, more selectivity in the targeting of benign versus malignant cells can be invoked. This increases the probability of successful treatment. The critical digitoxin level concentration, i.e. the concentration level where the number of living cells is not increasing, is approximately

Topics: Animals; Antineoplastic Agents; Calcium; Cell Count; Cell Division; Cell Line, Tumor; Computer Simulation; Digitoxin; Dose-Response Relationship, Drug; Humans; Mathematics; Mitosis; Models, Biological; Models, Theoretical; Neoplasms; Sensitivity and Specificity; Time Factors

For many drugs used in chemotherapy the difference between the therapeutic concentration and the toxic concentration is small. During treatment of a living organism from cancer by using chemotherapy, it is therefore important to foresee the therapeutic concentration in the organism as a function of the injected therapeutic drug dose. This article provides a mathematical dynamic description of the interaction between the organism and the drug, and analyses the dynamics by using ordinary differential equations. The model is tested in a clinical situation where digitoxin is used as the therapeutic drug. The agreement with this experiment is good.

Topics: Antineoplastic Agents; Digitoxin; Enzyme Inhibitors; Humans; Models, Theoretical; Neoplasms; Time Factors

Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population.. Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases.. The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract.. Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease. These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents.

Topics: Age Factors; Aged; Anti-Arrhythmia Agents; Case-Control Studies; Cohort Studies; Digitoxin; Dose-Response Relationship, Drug; Female; Heart Diseases; Humans; Incidence; Male; Neoplasms

The ability of digitalis to block cell proliferation has been well established for some time. Recently, digitalis in non-toxic concentrations has been showed to induce apoptosis in different malignant cell lines. In light of the pivotal role of apoptosis in cancer development and progression and this new experimental finding concerning digitalis, it seems probable that the apoptosis-inducing capability is explained by mechanisms other than just Na+/K+ ATPase inhibition. In this article, features of the cardiac glycosides which make them interesting to evaluate further as potential anticancer drugs are discussed. Some new data concerning inhibition and apoptosis in three human glioblastoma cell lines by digitoxin are also presented.

Topics: Antineoplastic Agents; Apoptosis; Digitalis Glycosides; Digitoxin; Enzyme Inhibitors; Humans; Models, Biological; Neoplasms; Sodium-Potassium-Exchanging ATPase; Tamoxifen; Tumor Cells, Cultured

Topics: Adolescent; Adult; Diagnosis, Differential; Digitalis; Estradiol Congeners; Gynecomastia; Humans; Hypogonadism; Infant, Newborn; Male; Middle Aged; Neoplasms; Plants, Medicinal; Plants, Toxic; Spironolactone; Testosterone; Testosterone Congeners