title: Enhancement of radiotherapy by oleandrin is a caspase-3 dependent process.
abstract: Cardiac glycosides such as digitoxin and ouabain have previously been shown to be selectively cytotoxic to tumor as opposed to normal cells. Moreover, this class of agents has also been shown to act as potent radiosensitizers. In the present study we explored the relative radiosensitization potential of oleandrin, a cardiac glycoside contained within the plant extract known as Anvirzel that recently underwent a Phase I trial as a novel drug for anticancer therapy. The data show that oleandrin produces an enhancement of sensitivity of PC-3 human prostate cells to radiation; at a cell survival of 0.1, the enhancement factor was 1.32. The magnitude of radiosensitization depended on duration of exposure of cells to drug prior to radiation treatment. While a radiosensitizing effect of oleandrin was evident with only 1h of cell exposure to drug, the effect greatly increased with 24h oleandrin pretreatment. Susceptibility of PC-3 cells to oleandrin and radiation-induced apoptosis was dependent on activation of caspase-3. Activation was greatest when cells were exposed simultaneously to oleandrin and radiation. Inhibition of caspase-3 activation with Z-DEVD-FMK abrogated the oleandrin-induced enhancement of radiation response suggesting that both oleandrin and radiation share a caspase-3 dependent mechanism of apoptosis in the PC-3 cell line.
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Nasu
authors.forename: Luka
authors.initials: L
authors.lastname: Milas
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kawabe
authors.forename: Uma
authors.initials: U
authors.lastname: Raju
authors.forename: Robert
authors.initials: R
authors.lastname: Newman
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D002298:Cardenolides / Q000737:chemistry* / Q000494:pharmacology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004792:Enzyme Precursors / Q000096:biosynthesis; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D008517:Phytotherapy; D011471:Prostatic Neoplasms / Q000473:pathology*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014410:Tumor Stem Cell Assay
chemical_list: C430926:Anvirzel; D002298:Cardenolides; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004792:Enzyme Precursors; D009363:Neoplasm Proteins; D009842:Oligopeptides; D011838:Radiation-Sensitizing Agents; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C021065:oleandrin