title: 7-formyl-10-methylisoellipticine, a novel ellipticine derivative, induces mitochondrial reactive oxygen species (ROS) and shows anti-leukaemic activity in mice.
abstract: Acute myeloid leukaemia (AML) is the most common type of leukaemia in adults and is associated with high relapse rates. Current treatment options have made significant progress but the 5 year survival for AML remains low and therefore, there is an urgent need to develop novel therapeutics. Ellipticines, a class of cancer chemotherapeutic agents, have had limited success clinically due to low solubility and toxic side effects. Isoellipticines, novel isomers of ellipticine, have been designed to overcome these limitations. One particular isoellipticine, 7-formyl-10-methylisoellipticine, has previously showed strong ability to inhibit the growth of leukaemia cell lines. In this study the anti-leukaemia effect of this compound was investigated in detail on an AML cell line, MV4-11. Over a period of 24 h 7-formyl-10-methyl isoellipticine at a concentration of 5 μM can kill up to 40 % of MV4-11 cells. Our research suggests that the cytotoxicity of 7-formyl-10-methylisoellipticine is partially mediated by an induction of mitochondrial reactive oxygen species (ROS). Furthermore, 7-formyl-10-methylisoellipticine demonstrated promising anti-tumour activity in an AML xenograft mouse model without causing toxicity, implying the potential of isoellipticines as novel chemotherapeutic agents in the treatment of leukaemia.
authors.affiliation: Tumour Biology Laboratory, School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Eileen G
authors.initials: EG
authors.lastname: Russell
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Chemistry and ABCRF, University College Cork, Cork, Ireland.
authors.forename: Elaine C
authors.initials: EC
authors.lastname: O'Sullivan
authors.affiliation: Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland.
authors.forename: Caitriona M
authors.initials: CM
authors.lastname: O'Driscoll
authors.affiliation: Department of Chemistry and ABCRF, University College Cork, Cork, Ireland.
authors.forename: Florence O
authors.initials: FO
authors.lastname: McCarthy
authors.affiliation: School of Biochemistry & Cell Biology, University College Cork, Cork, Ireland. t.cotter@ucc.ie.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Cotter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004611:Ellipticines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000611957:7-formyl-10-methylisoellipticine; D000970:Antineoplastic Agents; D004611:Ellipticines; D017382:Reactive Oxygen Species
keywords: 7-formyl-10-methylisoellipticine; AML; Isoellipticine; Leukaemia