Casiopeína IIgly-induced oxidative stress and mitochondrial dysfunction in human lung cancer A549 and H157 cells.
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)]NO(3) (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 microM) 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-IP(5+)), 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 over-production leading to mitochondrial dysfunction and cell death.
Kachadourian
Remy
R
Department of Medicine, National Jewish Health, Denver, CO 80206, USA. KachadourianR@njhealth.org
Brechbuhl
Heather M
HM
Ruiz-Azuara
Lena
L
Gracia-Mora
Isabel
I
Day
Brian J
BJ
D001059:Apoproteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002614:Chelating Agents / Q000138:chemical synthesis / Q000633:toxicity*; D003300:Copper / Q000737:chemistry; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D004579:Electron Transport / Q000187:drug effects; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000633:toxicity; D007501:Iron / Q000737:chemistry; D008175:Lung Neoplasms / Q000473:pathology; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000378:metabolism; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001059:Apoproteins; D002614:Chelating Agents; D004272:DNA, Mitochondrial; C045076:Fenton's reagent; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C505569:casiopeina II-glycine; D003300:Copper; D006861:Hydrogen Peroxide; D007501:Iron; D051547:Heme Oxygenase-1; D005978:Glutathione