Doxorubicin (DOX) is an anticancer anthracycline that presents a dose-dependent and cumulative cardiotoxicity as one of the most serious side effects. Several hypotheses have been advanced to explain DOX cardiac side effects, which culminate in the development of life-threatening cardiomyopathy. One of the most studied mechanisms involves the activation of DOX molecule into a more reactive semiquinone by mitochondrial Complex I, resulting in increased oxidative stress. The present review describes and critically discusses what is known about some of the potential mechanisms of DOX-induced cardiotoxicity including mitochondrial oxidative damage and loss of cardiomyocytes. We also discuss alterations of mitochondrial metabolism and the unique characteristics of DOX delayed toxicity, which can also interfere on how the cardiac muscle handles a "second-hit stress." We also present pharmaceutical and nonpharmaceutical approaches that may decrease DOX cardiac alterations in animal models and humans and discuss the limitations of each strategy.C 2013 Wiley Periodicals, Inc. Med. Res. Rev., 34, No. 1, 106-135, 2014

Metabolic regulation is largely dependent on mitochondria, which play an important role in energy homeostasis. Imbalance between energy intake and expenditure leads to mitochondrial dysfunction, characterized by a reduced ratio of energy production (ATP production) to respiration. Due to the role of mitochondrial factors/events in several apoptotic pathways, the possibility of targeting that organelle in the tumor cell, leading to its elimination is very attractive, although the safety issue is problematic. Berberine, a benzyl-tetra isoquinoline alkaloid extracted from plants of the Berberidaceae family, has been extensively used for many centuries, especially in the traditional Chinese and Native American medicine. Several evidences suggest that berberine possesses several therapeutic uses, including anti-tumoral activity. The present review supplies evidence that berberine is a safe anti-cancer agent, exerting several effects on mitochondria, including inhibition of mitochondrial Complex I and interaction with the adenine nucleotide translocator which can explain several of the described effects on tumor cells.

Glucose uptake and lipid metabolism are impaired in epicardial adipose tissue from heart failure patients with or without diabetes. Am J Physiol Endocrinol Metab 310: E550 -E564, 2016. First published January 26, 2016 doi:10.1152/ajpendo.00384.2015.-Type 2 diabetes mellitus is a complex metabolic disease, and cardiovascular disease is a leading complication of diabetes. Epicardial adipose tissue surrounding the heart displays biochemical, thermogenic, and cardioprotective properties. However, the metabolic cross-talk between epicardial fat and the myocardium is largely unknown. This study sought to understand epicardial adipose tissue metabolism from heart failure patients with or without diabetes. We aimed to unravel possible differences in glucose and lipid metabolism between human epicardial and subcutaneous adipocytes and elucidate the potential underlying mechanisms involved in heart failure. Insulin-stimulated [14 C]glucose uptake and isoproterenol-stimulated lipolysis were measured in isolated epicardial and subcutaneous adipocytes. The expression of genes involved in glucose and lipid metabolism was analyzed by reverse transcription-polymerase chain reaction in adipocytes. In addition, epicardial and subcutaneous fatty acid composition was analyzed by high-resolution proton nuclear magnetic resonance spectroscopy. The difference between basal and insulin conditions in glucose uptake was significantly decreased (P ϭ 0.006) in epicardial compared with subcutaneous adipocytes. Moreover, a significant (P Ͻ 0.001) decrease in the isoproterenol-stimulated lipolysis was also observed when the two fat depots were compared, and it was strongly correlated with lipolysis, lipid storage, and inflammation-related gene expression. Moreover, the fatty acid composition of these tissues was significantly altered by diabetes. These results emphasize potential metabolic differences between both fat depots in the presence of heart failure and highlight epicardial fat as a possible therapeutic target in situ in the cardiac microenvironment.

Sanguinarine is a natural isoquinoline alkaloid derived from the root of Sanguinaria canadensis and from other poppy fumaria species, and is known to have a broad spectrum of pharmacological properties. Here we have found that sanguinarine, at low micromolar concentrations, showed a remarkably rapid killing activity against human melanoma cells. Time-lapse videomicroscopy showed rapid morphological changes compatible with an apoptotic cell death, which was further supported by biochemical markers, including caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage and DNA breakdown. Pan-caspase inhibition blocked sanguinarine-induced cell death. Sanguinarine treatment also induced an increase in intracellular calcium concentration, which was inhibited by dantrolene, and promoted cleavage of BAP-31, thus suggesting a putative role for Ca(2+) release from endoplasmic reticulum and a cross-talk between endoplasmic reticulum and mitochondria in the anti-melanoma action of sanguinarine. Sanguinarine disrupted the mitochondrial transmembrane potential (ΔΨm), released cytochrome c and Smac/DIABLO from mitochondria to cytosol, and induced oxidative stress. Overexpression of Bcl-XL by gene transfer did not prevent sanguinarine-mediated cell death, oxidative stress or release of mitochondrial apoptogenic proteins. However, preincubation with N-acetyl-l-cysteine (NAC) prevented sanguinarine-induced oxidative stress, PARP cleavage, release of apoptogenic mitochondrial proteins, and cell death. Pretreatment with glutathione (GSH) also inhibited the anti-melanoma activity of sanguinarine. Thus, pretreatment with the thiol antioxidants NAC and GSH abrogated the killing activity of sanguinarine. Taking together, our data indicate that sanguinarine is a very rapid inducer of human melanoma caspase-dependent cell death that is mediated by oxidative stress.