A Combination of Cardamonin and Doxorubicin Selectively Affect Cell Viability of Melanoma Cells: An In Vitro Study.

Treatment of the most aggressive and deadliest form of skin cancer, the malignant melanoma, still has room for improvement. Its invasive nature and ability to rapidly metastasize and to develop resistance to standard treatment often result in a poor prognosis. While the highly effective standard chemotherapeutic agent doxorubicin (DOX) is widely used in a variety of cancers, systemic side effects still limit therapy.

The role of GAPDH in the selective toxicity of CNP in melanoma cells.

Background: Malignant melanoma is the most aggressive form of skin cancer with a rather poor prognosis. Standard chemotherapy often results in severe side effects on normal (healthy) cells finally being difficult to tolerate for the patients. Shown by us earlier, cerium oxide nanoparticles (CNP, nanoceria) selectively killed A375 melanoma cells while not being cytotoxic at identical concentrations on non-cancerous cells.

The Antimalarial Drug Artesunate Mediates Selective Cytotoxicity by Upregulating HO-1 in Melanoma Cells.

Despite great efforts to develop new therapeutic strategies to combat melanoma, the prognosis remains rather poor. Artesunate (ART) is an antimalarial drug displaying anti-cancer effects in vitro and in vivo. In this in vitro study, we investigated the selectivity of ART on melanoma cells.

The natural chalcone cardamonin selectively induces apoptosis in human neuroblastoma cells.

Neuroblastoma is the most common extracranial malignant tumor in childhood. Approximately 60% of all patients are classified as high-risk and require intensive treatment including non-selective chemotherapeutic agents leading to severe side effects. Recently, phytochemicals like the natural chalcone cardamonin (CD) have gained attention in cancer research.

Involvement of necroptosis in the selective toxicity of the natural compound (±) gossypol on squamous skin cancer cells in vitro.

Cutaneous basal and squamous cell carcinoma reflect the first and second most common type of non-melanoma skin cancer, respectively. Especially cutaneous squamous cell carcinoma has the tendency to metastasize, finally resulting in a rather poor prognosis. Therapeutic options comprise surgery, radiation therapy, and a systemic or targeted chemotherapy.

The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro.

A major challenge in current cancer therapy is still the treatment of metastatic melanomas of the skin. BH3 mimetics represent a novel group of substances inducing apoptosis. In this study, we investigated the cytotoxic effect of (±) gossypol (GP), a natural compound from cotton seed, on A375 melanoma cells and the underlying biochemical mechanisms.

In vitro selective cytotoxicity of the dietary chalcone cardamonin (CD) on melanoma compared to healthy cells is mediated by apoptosis.

Malignant melanoma is an aggressive type of cancer and the deadliest form of skin cancer. Even though enormous efforts have been undertaken, in particular the treatment options against the metastasizing form are challenging and the prognosis is generally poor. A novel therapeutical approach is the application of secondary plant constituents occurring in food and food products.

Redox-active cerium oxide nanoparticles protect human dermal fibroblasts from PQ-induced damage.

Recently, it has been published that cerium (Ce) oxide nanoparticles (CNP; nanoceria) are able to downregulate tumor invasion in cancer cell lines. Redox-active CNP exhibit both selective pro-oxidative and antioxidative properties, the first being responsible for impairment of tumor growth and invasion. A non-toxic and even protective effect of CNP in human dermal fibroblasts (HDF) has already been observed.

ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading.

Background & Aims: The pathogenesis of alcohol-induced liver disease (ALD) is poorly understood. Here, we examined the role of acid sphingomyelinase (ASMase) in alcohol induced hepatic endoplasmic reticulum (ER) stress, a key mechanism of ALD.

Methods: We examined ER stress, lipogenesis, hyperhomocysteinemia, mitochondrial cholesterol (mChol) trafficking and susceptibility to LPS and concanavalin-A in ASMase(-)(/-) mice fed alcohol.

Downregulation of tumor growth and invasion by redox-active nanoparticles.

Aims: Melanoma is the most aggressive type of malignant skin cancer derived from uncontrolled proliferation of melanocytes. Melanoma cells possess a high potential to metastasize, and the prognosis for advanced melanoma is rather poor due to its strong resistance to conventional chemotherapeutics. Nanomaterials are at the cutting edge of the rapidly developing area of nanomedicine.

Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis.

Background & Aims: Steatohepatitis (SH) is associated with mitochondrial dysfunction and excessive production of superoxide, which can then be converted into H(2)O(2) by SOD2. Since mitochondrial GSH (mGSH) plays a critical role in H(2)O(2) reduction, we explored the interplay between superoxide, H(2)O(2), and mGSH in nutritional and genetic models of SH, which exhibit mGSH depletion.

Methods: We used isolated mitochondria and primary hepatocytes, as well as in vivo SH models showing mGSH depletion to test the consequences of superoxide scavenging.

Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury.

Background & Aims: Liver steatosis enhances ischemia/reperfusion (I/R) injury and is considered a primary factor in graft failure after liver transplantation. Although previous reports have shown a role for qualitative steatosis (macrovesicular vs. microvesicular) in hepatic I/R injury, no studies have compared side by side the specific contribution of individual lipids accumulating in fatty liver to I/R damage.

PAI-1 plays a protective role in CCl4-induced hepatic fibrosis in mice: role of hepatocyte division.

Plasminogen activator inhibitor-1 (PAI-1) is an acute phase protein that has been shown to play a role in experimental fibrosis caused by bile duct ligation (BDL) in mice. However, its role in more severe models of hepatic fibrosis (e.g.

GD3 synthase overexpression sensitizes hepatocarcinoma cells to hypoxia and reduces tumor growth by suppressing the cSrc/NF-kappaB survival pathway.

Background: Hypoxia-mediated HIF-1alpha stabilization and NF-kappaB activation play a key role in carcinogenesis by fostering cancer cell survival, angiogenesis and tumor invasion. Gangliosides are integral components of biological membranes with an increasingly recognized role as signaling intermediates. In particular, ganglioside GD3 has been characterized as a proapoptotic lipid effector by promoting cell death signaling and suppression of survival pathways.

Redox control of liver function in health and disease.

Reactive oxygen species (ROS), a heterogeneous population of biologically active intermediates, are generated as by-products of the aerobic metabolism and exhibit a dual role in biology. When produced in controlled conditions and in limited quantities, ROS may function as signaling intermediates, contributing to critical cellular functions such as proliferation, differentiation, and cell survival. However, ROS overgeneration and, particularly, the formation of specific reactive species, inflicts cell death and tissue damage by targeting vital cellular components such as DNA, lipids, and proteins, thus arising as key players in disease pathogenesis.

Fibrin accumulation plays a critical role in the sensitization to lipopolysaccharide-induced liver injury caused by ethanol in mice.

Unlabelled: The early stages of alcohol-induced liver injury involve chronic inflammation. Whereas mechanisms by which this effect is mediated are not completely understood, it is hypothesized that enhanced sensitivity to circulating lipopolysaccharide (LPS) contributes to this process. It has recently been shown that ethanol induces activation of plasminogen activator inhibitor-1 (PAI-1).

PKCepsilon plays a causal role in acute ethanol-induced steatosis.

Steatosis is a critical stage in the pathology of alcoholic liver disease (ALD), and preventing steatosis could protect against later stages of ALD. PKCepsilon has been shown to contribute to hepatic steatosis in experimental non-alcoholic fatty liver disease (NAFLD); however, the role of PKCepsilon in ethanol-induced steatosis has not been determined. The purpose of this study was to therefore test the hypothesis that PKCepsilon contributes to ethanol-induced steatosis.

New role of resistin in lipopolysaccharide-induced liver damage in mice.

Studies in rodents suggest that the adipocytokine resistin causes insulin resistance via impairing normal insulin signaling. However, in humans, resistin may play a more important role in inflammation than in insulin resistance. Whether resistin contributes to inflammation in rodents is unclear.

Contribution of the sympathetic hormone epinephrine to the sensitizing effect of ethanol on LPS-induced liver damage in mice.

It is well known that ethanol preexposure sensitizes the liver to LPS hepatotoxicity. The mechanisms by which ethanol enhances LPS-induced liver injury are not completely elucidated but are known to involve an enhanced inflammatory response. Ethanol exposure also increases the metabolic rate of the liver, and this effect of ethanol on liver is mediated, at least in part, by the sympathetic hormone, epinephrine.

Subhepatotoxic exposure to arsenic enhances lipopolysaccharide-induced liver injury in mice.

Exposure to arsenic via drinking water is a serious health concern in the US. Whereas studies have identified arsenic alone as an independent risk factor for liver disease, concentrations of arsenic required to damage this organ are generally higher than found in the US water supply. The purpose of the current study was to test the hypothesis that arsenic (at subhepatotoxic doses) may also sensitize the liver to a second hepatotoxin.

Singlet oxygen inactivates protein tyrosine phosphatase-1B by oxidation of the active site cysteine.

Singlet oxygen ((1)O(2)), an electronically excited form of molecular oxygen, is a mediator of biological effects of ultraviolet A radiation, stimulating signaling cascades in human cells. We demonstrate here that (1)O(2) generated by photosensitization or by thermodecomposition of 3,3'-(1,4-naphthylidene)dipropionate-1,4-endoperoxide inactivates isolated protein tyrosine phosphatases (PTPases). PTPase activities of PTP1B or CD45 were abolished by low concentrations of (1)O(2), but were largely restored by post-treatment with dithiothreitol.

Extracellular generation of hydrogen peroxide is responsible for activation of EGF receptor by ultraviolet A radiation.

Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) have been proposed to be activated in cells exposed to ultraviolet A (UVA) radiation (320-400 nm) and to be involved in photocarcinogenesis. Singlet oxygen and hydrogen peroxide are being discussed as mediators of the activation of signal transduction pathways by UVA. It is demonstrated here that EGFR is not activated in cells exposed to UVA in the absence of extracellular photosensitizers.

Activation of ErbB2 by 2-methyl-1,4-naphthoquinone (menadione) in human keratinocytes: role of EGFR and protein tyrosine phosphatases.

Activation of ErbB receptor tyrosine kinases triggers multiple signaling pathways that regulate cellular proliferation and survival. We here demonstrate that ErbB2 is activated via the epidermal growth factor receptor (EGFR) upon exposure of cultured human keratinocytes to 2-methyl-1,4-naphthoquinone (menadione). Both ErbB2 and EGFR are shown to be regulated by protein tyrosine phosphatases that are inhibited by menadione, giving rise to the hypothesis that phosphatase inhibition by menadione may result in a net activation of EGFR and an enhanced ErbB2 phosphorylation.

Doxorubicin induces EGF receptor-dependent downregulation of gap junctional intercellular communication in rat liver epithelial cells.

Exposure of rat liver epithelial cells to doxorubicin, an anthraquinone derivative widely employed in cancer chemotherapy, led to a dose-dependent decrease in gap junctional intercellular communication (GJC). Gap junctions are clusters of inter-cellular channels consisting of connexins, the major connexin in the cells used being connexin-43 (Cx43). Doxorubicin-induced loss of GJC was mediated by activation of extracellular signal-regulated kinase (ERK)-1 and ERK-2, as demonstrated using inhibitors of ERK activation.