Induction of apoptosis by 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo- 11 H-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

Eun Jung Park, Evgeny Kiselev, Martin Conda-Sheridan, Mark Cushman, John M. Pezzuto

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)378-384
Number of pages7
JournalJournal of Natural Products
Volume75
Issue number3
DOIs
StatePublished - Mar 23 2012

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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