With recent insight into the mechanisms involved in diseases, such as cardiovascular disease, cancer, stroke, neurodegenerative diseases, and diabetes, more efficient modes of treatment are now being assessed. Traditional medicine including the use of natural products is widely practiced around the world, assuming that certain natural products contain the healing properties that may in fact have a preventative role in many of the diseases plaguing the human population. This paper reviews the biological effects of a group of natural compounds called polyphenols, including apigenin, epigallocatechin gallate, genistein, and (−)-epicatechin, with a focus on the latter. (−)-Epicatechin has several unique features responsible for a variety of its effects. One of these is its ability to interact with and neutralize reactive oxygen species (ROS) in the cell. (−)-Epicatechin also modulates cell signaling including the MAP kinase pathway, which is involved in cell proliferation. Mutations in this pathway are often associated with malignancies, and the use of (−)-epicatechin holds promise as a preventative agent and as an adjunct for chemotherapy and radiation therapy to improve outcome. This paper discusses the potential of some phenolic compounds to maintain, protect, and possibly reinstate health.

A growing body of evidence indicates that digitoxin cardiac glycoside is a promising anticancer agent when used at therapeutic concentrations. Digitoxin has a prolonged half-life and a well-established clinical profile. New scientific avenues have shown that manipulating the chemical structure of the saccharide moiety of digitoxin leads to synthetic analogs with increased cytotoxic activity. However, the anticancer mechanism of digitoxin or synthetic analogs is still subject to study while concerns about digitoxin's cardiotoxicity preclude its clinical application in cancer therapeutics. This review focuses on digitoxin and its analogs, and their cytotoxicity against cancer cells. Moreover, a new perspective on the pharmacological aspects of digitoxin and its analogs is provided to emphasize new research directions for developing potent chemotherapeutic drugs.

Digitoxin is a cardiac glycoside currently being investigated for potential use in oncology. While a number of structure-activity relationship studies have been conducted, an investigation of anticancer activity as a function of oligosaccharide chain length has not yet been performed. We generated mono-, di-, and tri-O-digitoxoside derivatives of digitoxin and compared their activity to the corresponding MeON-neoglycosides. Both classes of cardenolide derivatives display comparable oligosaccharide chain length-dependent cytotoxicity toward human cancer cell lines. Further investigation revealed that both classes of compounds induce caspase-9-mediated apoptosis in non-small cell lung cancer cells (NCI-H460). Since O-glycosides and MeON-neoglycosides share a similar mode of action, the convenience of MeON-neoglycosylation could be exploited in future SAR work to rapidly survey large numbers of carbohydrates to prioritize selected O-glycoside candidates for traditional synthesis.

Mechanisms of digitoxin-inhibited cell growth and induced apoptosis in human non-small cell lung cancer (NCI-H460) cells remain unclear. Understanding how digitoxin or derivate analogs induce their cytotoxic effect below therapeutically relevant concentrations will help in designing and developing novel, safer and more effective anti-cancer drugs. In this study, NCI-H460 cells were treated with digitoxin and a synthetic analog D6-MA to determine their anti-cancer activity. Different concentrations of digitoxin and D6-MA were used and the subsequent changes in cell morphology, viability, cell cycle, and protein expressions were determined. Digitoxin and D6-MA induced dose-dependent apoptotic morphologic changes in NCI-H460 cells via caspase-9 cleavage, with D6-MA possessing 5-fold greater potentcy than digitoxin. In comparison, non-tumorigenic immortalized bronchial and small airway epithelial cells displayed significantly less apoptotic sensitivity compared to NCI-H460 cells suggesting that both digitoxin and D6-MA were selective for NSCLC. Furthermore, NCI-H460 cells arrested in G(2)/M phase following digitoxin and D6-MA treatment. Post-treatment evaluation of key G2/M checkpoint regulatory proteins identified down-regulation of cyclin B1/cdc2 complex and survivin. Additionally, Chk1/2 and p53 related proteins experienced down-regulation suggesting a p53-independent cell cycle arrest mechanism. In summary, digitoxin and D6-MA exert anti-cancer effects on NCI-H460 cells through apoptosis or cell cycle arrest, with D6-MA showing at least 5-fold greater potency relative to digitoxin.

Pancreatic cancer is relatively radioresistant, however, radiotherapy has been shown to provide efficacy in the treatment of local disease. To increase the effectiveness of radiotherapy in pancreatic cancer, radiosensitizing drugs are under development. In this study, we investigated the radiosensitizing activity of the anti-diabetic drug metformin on pancreatic cancer cells in vitro. We demonstrated that metformin radiosensitized MiaPaCa-2 and Panc1 cells with radiation enhancement ratios (ER) ranging from 1.33–1.45 with metformin concentrations of 30–100 μM, and in addition, we showed that metformin sensitized cells to gemcitabine alone or in combination with radiation treatment. In addition, we found that pancreatic cancer stem cell-like cells showed enhanced radiosensitization in a tumorsphere assay with a REF of 1.66. At these radiosensitizing doses, metformin alone had low toxicity (as shown by >75% clonogenic survival) and did not affect cell cycle. The combination of metformin and radiation yielded greater numbers of γ-H2AX foci after 1 h compared to radiation alone, suggesting increased DNA damage signaling. Examination of the AMPK pathway showed that pharmacological inhibition of AMPK signaling or RNAi of AMPKα1 reversed metformin-mediated radiosensitization. These studies show that metformin radiosensitization of pancreatic cancer cells at micromolar concentration acts through AMPK and may affect DNA damage signaling. The data indicate that metformin may increase the efficacy of radiation therapy for pancreatic cancer.

Background Polycyclic aromatic hydrocarbons (PAHs) are potent atmospheric pollutants produced by incomplete combustion of organic materials. Pre-clinical and occupational studies have reported a positive association of PAHs with oxidative stress, inflammation and subsequent development of atherosclerosis, a major underlying risk factor for cardiovascular disease (CVD). The aim of the current study is to estimate the association between levels of PAH biomarkers and CVD in a national representative sample of United States (US) adults. Methods We examined adult participants (≥20 years of age) from the merged US National Health and Nutrition Examination Survey 2001–2010. Logistic regression models were used to estimate the associations of each urinary PAH biomarker and CVD. Post-exploratory structural equation modeling was then used to address the interdependent response variables (angina, heart attack, stroke and coronary heart disease) as well as the interdependencies of PAH biomarkers. Results PAH biomarkers were positively associated with cardiovascular disease in multiple logistic regression models, although some associations were not statistically robust. Using structural equation modelling, latent PAH exposure variable was positively associated with latent CVD level variable in the multivariable adjusted model (β = 0.12; 95% CI: 0.03, 0.20). Conclusion A modest association between levels of PAH biomarkers and CVD was detected in US adults. Further prospective studies with adequate sample size are needed to replicate or refute our findings.

Radiotherapy is the treatment of choice for solid tumors including pancreatic cancer, but the effectiveness of treatment is limited by radiation resistance. Resistance to chemotherapy or radiotherapy is associated with reduced mitochondrial respiration and drugs that stimulate mitochondrial respiration may decrease radiation resistance. The objectives of this study were to evaluate the potential of (-)-epicatechin to stimulate mitochondrial respiration in cancer cells and to selectively sensitize cancer cells to radiation. We investigated the natural compound (-)-epicatechin for effects on mitochondrial respiration and radiation resistance of pancreatic and glioblastoma cancer cells using a Clark type oxygen electrode, clonogenic survival assays, and Western blot analyses. (-)-Epicatechin stimulated mitochondrial respiration and oxygen consumption in Panc-1 cells. Human normal fibroblasts were not affected. (-)-Epicatechin sensitized Panc-1, U87, and MIA PaCa-2 cells with an average radiation enhancement factor (REF) of 1.7, 1.5, and 1.2, respectively. (-)-Epicatechin did not sensitize normal fibroblast cells to ionizing radiation with a REF of 0.9, suggesting cancer cell selectivity. (-)-Epicatechin enhanced Chk2 phosphorylation and p21 induction when combined with radiation in cancer, but not normal, cells. Taken together, (-)-epicatechin radiosensitized cancer cells, but not normal cells, and may be a promising candidate for pancreatic cancer treatment when combined with radiation.

Objective Pre-clinical studies have reported acute cardiovascular effects of cannabis including a dose-dependent increase in blood pressure while orthostatic hypotension may follow as a result of decreased vascular resistance. In case reports, evidence links cannabis with acute cardiovascular events in young and middle aged adults. Here, we offer epidemiologic estimates on cannabis use-blood pressure levels association from the United States (US) National Health and Nutrition Examination Surveys 2005–2012 (n=12426). Methods Computer-assisted self-interviews assessed cannabis use. Blood pressure was determined by an average of up to four measurements taken during a single examination. Regression modeling was used to examine cannabis use– blood pressure association. Results Recently active cannabis use was associated with increase in systolic blood pressure (β = 1.6; 95% CI: 0.6, 2.7) in the age-sex adjusted model. Additional covariate adjustment did not affect the positive association. No association between cannabis use and diastolic blood pressure was detected. Conclusion A modest association between recent cannabis use and systolic blood pressure was detected among a relatively large nationally representative sample of US adults. With the legalization of cannabis, there a need for pre-clinical, clinical and prospective population-based research on the cardiovascular effects of cannabis use.