title: Ellipticine induces apoptosis in T-cell lymphoma via oxidative DNA damage.
abstract: The tumor suppressor p53 is often mutated in human cancers. Restoring its antitumor activity has been shown to be a promising therapeutic approach for cancer treatment. Here we analyzed the activity and mechanism of a p53 reactivator, ellipticine, in a cellular model of cutaneous T-cell lymphoma (CTCL), a disease that is progressive, chemoresistant and refractory to treatment. We tested the effect of ellipticine in three cell lines with different p53 status: MyLa2000 (p53(wt/wt)), SeAx ((G245S)p53) and Hut-78 ((R196Stop)p53). Ellipticine caused apoptosis in MyLa2000 and SeAx and restored the transcriptional activity of (G245S)p53 in SeAx. However, p53 siRNA knockdown experiments revealed that p53 was not required for ellipticine-induced apoptosis in CTCL. The lipophilic antioxidant α-tocopherol inhibited ellipticine-dependent apoptosis and we linked the apoptotic response to the oxidative DNA damage. Our results provide evidence that ellipticine-induced apoptosis is exerted through DNA damage and does not require p53 activation in T-cell lymphoma.
authors.affiliation: Department of Dermatology, Bispebjerg Hospital , Copenhagen , Denmark.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Savorani
authors.forename: Valentina
authors.initials: V
authors.lastname: Manfé
authors.forename: Edyta
authors.initials: E
authors.lastname: Biskup
authors.forename: Robert
authors.initials: R
authors.lastname: Gniadecki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D009154:Mutation; D034622:RNA Interference; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D004611:Ellipticines; D016159:Tumor Suppressor Protein p53; C034192:ellipticine; D024502:alpha-Tocopherol
keywords: DNA damage; Ellipticine; apoptosis; cutaneous T-cell lymphoma; p53