Epicatechin Stimulates Mitochondrial Activity and Selectively Sensitizes Cancer Cells to Radiation

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

The association of urinary polycyclic aromatic hydrocarbon biomarkers and cardiovascular disease in the US population

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 modeling, 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

Digitoxin and its analogs as novel cancer therapeutics

Abstract 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.</p

Molecular Mechanisms and Therapeutic Effects of (−)-Epicatechin and Other Polyphenols in Cancer, Inflammation, Diabetes, and Neurodegeneration

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

(-)-Epicatechin does not sensitize normal cells to radiation.

<p>(A) 20 µM (-)-Epicatechin does not sensitize HNF cells to radiation (REF = 0.9). (B) (-)-Epicatechin alone does not inhibit colony formation in HNF (p>0.05).</p

(-)-Epicatechin inhibits p21 expression and does not stimulate checkpoint kinase protein 2 phosphorylation at threonine 68 in HNF cells.

<p>(A) (-)-Epicatechin inhibits p21 expression. Protein levels in 20 µM (-)-epicatechin treated samples were normalized to samples treated with 6 Gy, and *p<0.05. (B) 20 µM (-)-epicatechin does not stimulate Chk2 phosphorylation. Protein levels in (-)-epicatechin treated samples were normalized to samples that were treated with 6 Gy.</p

(-)-Epicatechin is a flavanol that selectively stimulates mitochondrial respiration in pancreatic cancer cells.

<p>(A) Oxygen consumption by cytochrome c oxidase (COX) from Panc-1 cells exposed to different (-)-epicatechin concentrations. Turnover is defined as consumed O₂ (nM)/(min · total protein (mg)). Respiration rates are increased by (-)-epicatechin in a concentration-dependent manner. *p<0.05, compared to 0 µM (-)-epicatechin. (B) Oxygen consumption by cytochrome c oxidase (COX) from human normal fibroblast (HNF) cells exposed to 0 or 100 µM (-)-epicatechin. Respiration rates are not increased by 100 µM (-)-epicatechin.</p

The effect of (-)-epicatechin on ETC protein expression in combination with radiation.

<p>(A) A representative blot for ETC protein expression in Panc-1 cells that were treated with 0–200 µM (-)-epicatechin and 0 or 6 Gy. (B) (-)-Epicatechin alone does not significantly change ETC protein expression. Protein levels are normalized to the untreated control. (B) (-)-Epicatechin induced minimal changes in ETC protein expression when combined with 6 Gy. Values were normalized to 6 Gy alone, and * p<0.05 relative to 6 Gy/0 µM (-)-epicatechin.</p

(-)-Epicatechin sensitizes cancer cells to radiation.

<p>(A) (-)-Epicatechin sensitizes Panc-1 cells to radiation with an average REF = 1.7 (B) (-)-Epicatechin sensitizes U87 cells to radiation with an average REF of 1.5. (C) (-)-Epicatechin sensitizes MIA PaCa-2 cells to radiation with an average REF = 1.2.</p

(-)-Epicatechin stimulates checkpoint kinase protein 2 phosphorylation at threonine 68 and p21 expression in Panc-1 cells.

<p>(A) (-)-Epicatechin stimulates p21 expression. Protein levels in 20 µM (-)-epicatechin treated samples were normalized to samples treated with 6 Gy. (B) 20 µM (-)-epicatechin stimulates Chk2 phosphorylation. Protein levels in (-)-epicatechin treated samples were normalized to samples that were treated with 6 Gy, and *p<0.05.</p