Novel synthetic triterpenoid methyl 25-hydroxy-3-oxoolean-12-en-28-oate induces apoptosis through JNK and p38 MAPK pathways in human breast adenocarcinoma MCF-7 cells.

Abstract

Breast cancer is the most common neoplasm in women and is the leading cause of cancer-related death for women. Therefore, new agents targeting prevention and treatment of breast cancer are urgently needed. The present study first investigates that a novel triterpenoid Methyl 25-Hydroxy-3-oxoolean-12-en-28-oate (AMR-Me) derived from 25-Hydroxy-3-oxoolean-12-en-28-oic acid (AMR) is a potent inhibitor of cell growth by inducing human breast cancer MCF-7 cells to undergo apoptosis. AMR-Me induced DNA fragmentation and PARP degradation which were preceded by changing Bax/Bcl-2 ratios, cytochrome c release, and subsequent induction of pro-caspase-9 and -7 processing in breast carcinoma MCF-7 cells, but it did not act on Fas/Fas ligand pathways and the activation of caspase-8, suggesting AMR-Me triggered the mitochondrial apoptotic pathway. The general caspase blocking peptide VAD partially blocked AMR-Me induced apoptosis. AMR-Me stimulated p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase (JNK), but not extracellular signal-regulated kinase activation during apoptosis. SP600125, a specific inhibitor for JNK and SB203580, a p38 MAPK-specific inhibitor suppressed AMR-Me induced apoptosis indicating that activation of JNK and p38 MAPKs involved in the mitochondrial activation-mediated cell death pathway. Our results suggest that AMR-Me can utilize two different MAPK signaling pathways for amplifying the apoptosis cascade, is critical for both our understanding of cell death events and development of cancer preventive/therapeutic agents.

• Authors: Thangaiyan Rabi, Sipra Banerjee
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 47 Issue 6 Pg. 415-23 (Jun 2008) ISSN: 1098-2744 [Electronic] United States
• PMID: 18058803 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: (c) 2007 Wiley-Liss, Inc.

Chemical References

• Protein Kinase Inhibitors
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• methyl 25-hydroxy-3-oxoolean-12-en-28-oate
• Oleanolic Acid
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4

Topics

• Adenocarcinoma (enzymology, pathology)
• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Humans
• MAP Kinase Kinase 4 (antagonists & inhibitors, metabolism)
• Mice
• Mice, Inbred BALB C
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• RNA, Small Interfering
• Tumor Suppressor Protein p53 (genetics)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)