title: Oleandrin-mediated oxidative stress in human melanoma cells.
abstract: While certain cardiac glycoside compounds such as oleandrin, bufalin and digitoxin are known to be associated with potent cytotoxicity to human tumor cells, the mechanisms by which this effect is produced are not clear. We now demonstrate that incubation of human malignant melanoma BRO cells with oleandrin results in a time-dependent formation of reactive oxygen species (ROS). Use of Mito-SOX and dihydroethidine dyes revealed the presence of oleandrin-mediated superoxide anions. Formation of superoxide anions correlated with a loss in cellular viability, proliferation and cellular defense mechanisms such as GSH content. Oleandrin also resulted in an unusual time-dependent mitochondrial condensation in BRO cells that could be blocked with use of N-acetyl cysteine (NAC). NAC was also shown to block ROS formation and partially prevent oleandrin-mediated loss of cellular GSH. Taken as a whole, the data suggest that exposure of human tumor cells such as BRO to oleandrin results in the formation of superoxide anion radicals that mediate mitochondrial injury and loss of cellular GSH pools. These mechanisms play a role in cardiac glycoside mediated tumor cell injury. Conversely, incubation of NAC, a precursor to GSH, largely prevents oleandrin-mediated inhibition of proliferation and mitochondria structural changes.
authors.affiliation: Department of Experimental Therapeutics, Univ. Texas M. D. Anderson Cancer Center, Houston, TX 77054, USA. rnewman@mdanderson.org
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Dah Hsi
authors.initials: DH
authors.lastname: Ho
authors.forename: Dan
authors.initials: D
authors.lastname: Ni
authors.forename: Diana
authors.initials: D
authors.lastname: Chan
authors.forename: Mary
authors.initials: M
authors.lastname: Vijjeswarapu
authors.forename: Carrie
authors.initials: C
authors.lastname: Cartwright
authors.forename: Susan
authors.initials: S
authors.lastname: Dixon
authors.forename: Edward
authors.initials: E
authors.lastname: Felix
authors.forename: Crandell
authors.initials: C
authors.lastname: Addington
mesh_terms: D002298:Cardenolides / Q000494:pharmacology*; D049109:Cell Proliferation; D003553:Cystine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D002298:Cardenolides; D017382:Reactive Oxygen Species; D003553:Cystine; C021065:oleandrin; C030905:N-monoacetylcystine