Betulinic acid suppresses constitutive and TNFalpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells.

Abstract

Development of chemoresistance in androgen-refractory prostate cancer cells is partly due to constitutive activation of Rel/NF-kappaB transcription factors that regulate several cell survival and anti-apoptotic genes. In this study we examined whether betulinic acid (BetA), a pentacyclic triterpene from the bark of white birch, is effective in inhibiting NF-kappaB expression in androgen-refractory human prostate cancer cells exhibiting high constitutive NF-kappaB expression. Treatment of PC-3 cells with BetA inhibited DNA binding and reduced nuclear levels of the NF-kappaB/p65. BetA-mediated NF-kappaB inhibition involved decreased IKK activity and phosphorylation of IkappaBalpha at serine 32/36 followed by its degradation. Reporter assays revealed that NF-kappaB inhibition by BetA is transcriptionally active. These effects were found to correlate with a shift in Bax/Bcl-2 ratio and cleavage of poly(ADP)ribose polymerase more towards apoptosis. BetA also inhibited TNFalpha-induced activation of NF-kappaB via the IkappaBalpha pathway, thereby sensitizing the cells to TNFalpha-induced apoptosis. Our studies demonstrate that BetA effectively inhibits constitutive NF-kappaB activation and supports the rationale for targeting NF-kappaB through combination protocols with BetA in androgen-refractory prostate cancer.

• Authors: Thangaiyan Rabi, Sanjeev Shukla, Sanjay Gupta
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 47 Issue 12 Pg. 964-73 (Dec 2008) ISSN: 1098-2744 [Electronic] United States
• PMID: 18444250 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents, Phytogenic
• Formazans
• NF-kappa B
• Pentacyclic Triterpenes
• Tetrazolium Salts
• Triterpenes
• Tumor Necrosis Factor-alpha
• MTT formazan
• Luciferases
• Betulinic Acid

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Formazans (metabolism)
• Genes, Reporter
• Humans
• Luciferases (metabolism)
• Male
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Pentacyclic Triterpenes
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Tetrazolium Salts (metabolism)
• Time Factors
• Transfection
• Triterpenes (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Betulinic Acid