7-formyl-10-methylisoellipticine, a novel ellipticine derivative, induces mitochondrial reactive oxygen species (ROS) and shows anti-leukaemic activity in mice
- 376 Downloads
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.
KeywordsIsoellipticine 7-formyl-10-methylisoellipticine Leukaemia AML
This work was supported by the Programme for Research in Third-Level Institutions (PRTLI), the Irish Cancer Society and the Children’s Leukaemia Research Project, the Irish Research Council by means of an IRCSET scholarship award and the Government of Ireland Postdoctoral Fellowship from Irish Research Council (GOIPD/2013/150).
Compliance with ethical standards
All animal experimental procedures were approved by the ethical committee at the University College Cork and performed in accordance with the European Union (Protection of Animals Used for Scientific Purposes) Regulations 2012 (S.I. No. 543 of 2012) and Directive 2010/63/EU for animals used for scientific purposes.
Conflict of interest
The authors declare that they have no conflict of interest.
- 5.Handin RI, Lux SE, Stosse TP, Babior BM (2003) Blood: principles and practice of hematology, 2nd edn. Lippincott, Williams and Wilkins, Philidelphia, pp 483–530Google Scholar
- 11.O’Sullivan EC, Miller CM, Deane FM, McCarthy FO (2012) Emerging targets in the bioactivity of ellipticines and derivatives. Studies in natural products chemistry, Chapter 6, p189–226. Amsterdam, Netherlands: Elsevier Science PublishersGoogle Scholar
- 22.Gozgit JM, Wong MJ, Wardwell S, Tyner JW, Loriaux MM, Mohemmad QK, Narasimhan NI, Shakespeare WC, Wang F, Druker BJ, Clackson T, Rivera VM (2011) Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther 10:1028–1035PubMedPubMedCentralCrossRefGoogle Scholar
- 28.Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS, Holland JF, Frei E (eds) (2003) Cancer medicine, 6th edn. BC Decker Inc, Hamilton, pp 1747–1768Google Scholar
- 31.Stanley JW, Rosenbaum EE (2005) The toxicology of Dimethyl Sulfoxide (DMSO). Headache J Head Face Pain 6(3):127–136Google Scholar
- 32.Solanki SS, Soni LK, Maheshwari RW (2013) Study on mixed solvency concept in formulation development of aqueous injection of poorly water soluble drug. J Pharm 678132Google Scholar
- 37.Roboz GJ (2011) Novel approaches to the treatment of acute myeloid leukemia. Hematol Am Soc Hematol Educ Prog 43–50Google Scholar
- 38.Vick B, Rothenberg M, Sandhöfer N, Carlet M, Finkenzeller C, Krupka C, Grunert M, Trumpp A, Corbacioglu S, Ebinger M, André MC, Hiddemann W, Schneider S, Subklewe M, Metzeler KH, Spiekermann K, Jeremias I (2015) An advanced preclinical mouse model for acute myeloid leukemia using patients’ cells of various genetic subgroups and in vivo bioluminescence imaging. PLoS One 10:0120925CrossRefGoogle Scholar