Hydroxychavicol, a betel leaf component, inhibits prostate cancer through ROS-driven DNA damage and apoptosis.

Abstract

Dietary phytochemicals are excellent ROS-modulating agents and have been shown to effectively enhance ROS levels beyond toxic threshold in cancer cells to ensure their selective killing while leaving normal cells unscathed. Here we demonstrate that hydroxychavicol (HC), extracted and purified from Piper betel leaves, significantly inhibits growth and proliferation via ROS generation in human prostate cancer, PC-3 cells. HC perturbed cell-cycle kinetics and progression, reduced clonogenicity and mediated cytotoxicity by ROS-induced DNA damage leading to activation of several pro-apoptotic molecules. In addition, HC treatment elicited a novel autophagic response as evidenced by the appearance of acidic vesicular organelles and increased expression of autophagic markers, LC3-IIb and beclin-1. Interestingly, quenching of ROS with tiron, an antioxidant, offered significant protection against HC-induced inhibition of cell growth and down regulation of caspase-3, suggesting the crucial role of ROS in mediating cell death. The collapse of mitochondrial transmembrane potential by HC further revealed the link between ROS generation and induction of caspase-mediated apoptosis in PC-3 cells. Our data showed remarkable inhibition of prostate tumor xenografts by ~72% upon daily oral administration of 150mg/kg bw HC by quantitative tumor volume measurements and non-invasive real-time bioluminescent imaging. HC was well-tolerated at this dosing level without any observable toxicity. This is the first report to demonstrate the anti-prostate cancer efficacy of HC in vitro and in vivo, which is perhaps attributable to its selective prooxidant activity to eliminate cancer cells thus providing compelling grounds for future preclinical studies to validate its potential usefulness for prostate cancer management.

• Authors: Sushma Reddy Gundala, Chunhua Yang, Rao Mukkavilli, Rutugandha Paranjpe, Meera Brahmbhatt, Vaishali Pannu, Alice Cheng, Michelle D Reid, Ritu Aneja
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 280 Issue 1 Pg. 86-96 (Oct 01 2014) ISSN: 1096-0333 [Electronic] United States
• PMID: 25064160 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Reactive Oxygen Species
• 2-hydroxychavicol
• Eugenol

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Cell Line, Tumor
• DNA Damage (drug effects, physiology)
• Dose-Response Relationship, Drug
• Eugenol (analogs & derivatives, isolation & purification, pharmacology, therapeutic use)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Piper betle
• Plant Leaves
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays (methods)