title: Induction of apoptosis by 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline via modulation of MAPKs (p38 and c-Jun N-terminal kinase) and c-Myc in HL-60 human leukemia cells.
abstract: Recently, we reported that 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (AM6-36), sharing structural similarity with naturally occurring isoquinolines, induced activities mediated by retinoid X receptor (RXR) response element accompanied by antiproliferative effects on breast cancer cells. To further characterize the biologic potential of AM6-36, we currently report studies conducted with HL-60 human leukemia cells. AM6-36 significantly inhibited cellular proliferation in a dose- and time-dependent manner with an IC(50) value of 86 nM. When evaluated at low test concentrations (≤0.25 μM), AM6-36 induced arrest in the G2/M phase of the cell cycle. At higher concentrations (1 and 2 μM), the response shifted to apoptosis, which was consistent with the effect of AM6-36 on other apoptotic signatures including an increase of apoptotic annexin V(+) 7-AAD(-) cells, loss of mitochondrial membrane potential, induction of poly(ADP-ribose) polymerase cleavage, and activation of several caspases. These apoptotic effects are potentially due to up-regulation of p38 MAPK and JNK phosphorylation and down-regulation of c-Myc oncogene expression. Taken together, AM6-36 might serve as an effective anticancer agent by inducing G2/M cell cycle arrest and apoptosis through the activation of MAPKs and inhibition of c-Myc.
authors.affiliation: College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii 96720, United States.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Evgeny
authors.initials: E
authors.lastname: Kiselev
authors.forename: Martin
authors.initials: M
authors.lastname: Conda-Sheridan
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007192:Indenes / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D015394:Molecular Structure; D047488:Retinoid X Receptors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C559481:3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno(1,2-c)isoquinoline; D007192:Indenes; D007546:Isoquinolines; D047488:Retinoid X Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases