A novel parthenin analog exhibits anti-cancer activity: activation of apoptotic signaling events through robust NO formation in human leukemia HL-60 cells.

Abstract

This study describes the anti-cancer activity of P19, an analog of parthenin. P19 induced apoptosis in HL-60 cells and inhibited cell proliferation with 48h IC50 of 3.5μM. At 10mg/kg dose, it doubled the median survival time of L1210 leukemic mice and at 25mg/kg it inhibited Ehrlich ascites tumor growth by 60%. Investigation of the mechanism of P19 induced apoptosis in HL-60 cells revealed that N-acetyl-l-cysteine (NAC) and s-methylisothiourea (sMIT) could reverse several molecular events that lead to cell death by inhibiting nitric oxide (NO) formation. It selectively produced massive NO in cells while quenching the basal ROS levels with concurrent elevation of GSH. P19 disrupted mitochondrial integrity leading to cytochrome c release and caspase-9 activation. P19 also caused caspase-8 activation by selectively elevating the expression of DR4 and DR5. All these events lead to the activation of caspase-3 leading to PARP-1 cleavage and DNA fragmentation. However, knocking down of AIF by siRNA also suppressed the apoptosis substantially thus indicating caspase independent apoptosis, too. Further, contrary to enhanced iNOS expression, its transcription factor, NF-κB (p65) was cleaved with a simultaneous increase in cytosolic IκB-alpha. In addition, P19 potently inhibited pro-survival proteins pSTAT3 and survivin. The multi-modal pro-apoptotic activity of P19 raises its potential usefulness as a promising anti-cancer therapeutic.

• Authors: Ajay Kumar, Fayaz Malik, Shashi Bhushan, Bhahwal A Shah, Subhash C Taneja, Harish C Pal, Zahoor A Wani, Dilip M Mondhe, Jagdeep Kaur, Jaswant Singh
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 193 Issue 3 Pg. 204-15 (Sep 30 2011) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 21741372 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 2'-(4-chlorophenyl)-3-(4-chlorophenylidene)-5,10-dimethyl-12-methylene-decahydro-1,2-(1',3'-dioxocyclopenta(c))azuleno(4,5-b)furan-4,11-dione
• Antineoplastic Agents
• Apoptosis Inducing Factor
• BIRC5 protein, human
• Bridged-Ring Compounds
• Inhibitor of Apoptosis Proteins
• NF-kappa B
• RNA, Small Interfering
• STAT3 Transcription Factor
• Sesquiterpenes
• Survivin
• Nitric Oxide
• Cytochromes c
• Nitric Oxide Synthase Type II
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Caspase 3
• Caspase 8
• Caspase 9
• Glutathione
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis
• Apoptosis Inducing Factor (antagonists & inhibitors, genetics, metabolism)
• Bridged-Ring Compounds (chemistry, pharmacology)
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Cytochromes c (metabolism)
• Female
• Glutathione (metabolism)
• HL-60 Cells
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Male
• Mice
• NF-kappa B (metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• STAT3 Transcription Factor (metabolism)
• Sesquiterpenes (chemistry, pharmacology)
• Signal Transduction
• Survivin