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1.  Chrysin enhances doxorubicin-induced cytotoxicity in human lung epithelial cancer cell lines: the role of glutathione 
We hypothesized that flavonoid-induced glutathione (GSH) efflux through multi-drug resistance proteins (MRPs) and subsequent intracellular GSH depletion is a viable mechanism to sensitize cancer cells to chemotherapies. This concept was demonstrated using chrysin (5–25 μM) induced GSH efflux in human non-small cell lung cancer lines exposed to the chemotherapeutic agent, doxorubicin (DOX). Treatment with chrysin resulted in significant and sustained intracellular GSH depletion and the GSH enzyme network in the four cancer cell types was predictive of the severity of chrysin induced intracellular GSH depletion. Gene expression data indicated a positive correlation between basal MRP1, MRP3 and MRP5 expression and total GSH efflux before and after chrysin exposure. Co-treating the cells for 72 hours with chrysin (5–30 μM) and DOX (0.025–3.0 μM) significantly enhanced the sensitivity of the cells to DOX as compared to 72-hour DOX alone treatment in all four cell lines. The maximum decrease in the IC50 values of cells treated with DOX alone compared to co-treatment with chrysin and DOX was 43% in A549 cells, 47% in H157 and H1975 cells and 78% in H460 cells. Chrysin worked synergistically with DOX to induce cancer cell death. This approach could allow for use of lower concentrations and/or sensitize cancer cells to drugs that are typically resistant to therapy.
PMCID: PMC3257857  PMID: 21856323
Chrysin; flavonoids; glutathione; multidrug resistance proteins; adriamycin; non small cell carcinoma
2.  Context-Dependent Differentiation of Multipotential Keratin 14–Expressing Tracheal Basal Cells 
Multipotential (MP) differentiation is one characteristic of a tissue-specific stem cell (TSC). Lineage tracing of tracheobronchial basal cells after naphthalene (NA) injury or in the postnatal period demonstrated that basal cells were MP progenitors for Clara-like and ciliated cells. These studies, as well as reports of spatially restricted, label-retaining basal cells, and MP differentiation by human bronchial cells support the hypothesis that a TSC maintained and repaired the tracheobronchial epithelium. However, differences in basal cell phenotype (keratin [K] 5+ versus K14+), age (postnatal versus adult), health status (normal versus injured), and injury type (acid, detergent, NA) limited comparisons among studies and thus diminished the strength of the TSC argument. The finding that K14 was up-regulated after NA injury was a caveat to our previous analysis of reparative (r)K14-expressing cells (EC). Thus, the present study lineage traced steady-state (s)K14EC and evaluated differentiation potential in the normal and repairing epithelium. We showed that sK14EC were unipotential in the normal epithelium and MP after NA, sK14EC-dervied clones were not restricted to putative TSC niches, sK14EC cells were a direct progenitor for Clara-like and ciliated cells, MP-sK14EC clones accumulated over time, and sK14EC-derived Clara-like cells were progenitors for ciliated cells.
PMCID: PMC3175566  PMID: 21131447
basal; clara-like; ciliated; differentiation potential; lineage tracing; tissue-specific stem cell
3.  Casiopeína IIgly-induced oxidative stress and mitochondrial dysfunction in human lung cancer A549 and H157 cells 
Toxicology  2009;268(3):176-183.
Casiopeínas are a series of mixed chelate copper complexes that are being evaluated as anticancer agents. Their effects in the cell include oxidative damage and mitochondrial dysfunction, yet the molecular mechanisms leading to such effects remain unclear. We tested whether [Cu(4,7-dimethyl-phenanthroline)(glycinate)]NO3 (Casiopeína IIgly or Cas IIgly) could alter cellular glutathione (GSH) levels by redox cycling with GSH to generate ROS and cellular oxidative stress. Cas IIgly induced a dramatic drop in intracellular levels of GSH in human lung cancer H157 and A549 cells, and is able to use GSH as source of electrons to catalyze the Fenton reaction. In both cell lines, the toxicity of Cas IIgly (2.5–5 μM) was potentiated by the GSH synthesis inhibitor L-buthionine sulfoximine (BSO) and diminished by the catalytic antioxidant manganese(III) meso-tetrakis(N,N′-diethylimidazolium-2-yl)porphyrin (MnTDE-1,3-IP5+), thus supporting an important role for oxidative stress. Cas IIgly also caused an over-production of reactive oxygen species (ROS) in the mitochondria and a depolarization of the mitochondrial membrane. Moreover, Cas IIgly produced mitochondrial DNA damage that resulted in an imbalance of the expression of the apoproteins of the mitochondrial respiratory chain, which also can contribute to increased ROS production. These results suggest that Cas IIgly initiates multiple possible sources of ROS overproduction leading to mitochondrial dysfunction and cell death.
PMCID: PMC2826547  PMID: 20026372
copper-phenanthroline; glutathione; catalytic antioxidant; mtDNA; H157; A549
4.  Select cyclopentenone prostaglandins trigger glutathione efflux and the role of ABCG2 transport 
Free radical biology & medicine  2009;47(6):722-730.
Electrophilic cyclopentenone prostaglandins (cyPGs), such as 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2), initiate redox-based cell signaling responses including increased intracellular glutathione (GSH) synthesis. We investigated whether cyPGs facilitated GSH efflux and if members of the ATP-cassette binding (ABC) protein family mediated the efflux. Four human cell lines were treated with 1-6μM of cyPGs for 48 hours. Media and cells were harvested for GSH measurements using HPLC-EC. CyPG treatment increased extracellular GSH levels 2- to 3-fold over controls in HN4 and C38 cells and 5- to 6-fold in SAEC and MDA 1586 cells and were dependent on increased GSH synthesis. Our studies show that prostaglandin D2 (PGD2) and its metabolites, prostaglandin J2 (PGJ2) and 15dPGJ2 specifically induce GSH efflux as compared to other eicosanoids. These higher extracellular GSH levels were associated with protection from tert-butyl hydroperoxide. Superarray analysis of ABC transporters suggested only ABCG2 expression had a positive relationship in the 4 cell types when compared with extracellular GSH increases after cyPG treatment. The ABCG2 substrate Hoechst 33342 inhibited extracellular GSH increase after 15dPGJ2 treatment. We report for the first time that ABCG2 may play a role in GSH efflux in response to cyPG treatment, and may link inflammatory signaling with antioxidant adaptive responses.
PMCID: PMC2730198  PMID: 19520157
15-deoxy-Δ12,14-prostaglandin J2; ABC proteins; ATP-cassette transporter proteins; BCRP; breast cancer resistance protein; glutathione; prostaglandins

Results 1-4 (4)