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 150 mg/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 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.

Pro-oxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy

“…effects[111]. Although this study also showed that hydroxychavicol increases the levels ofROS in vitro leading to DNA damage, collapse of mitochondrial transmembrane potential, apoptosis and cell cycle arrest, further experiments are necessary to demonstrate the prooxidant role of this polyphenol in vivo.…”

Tolcapone induces oxidative stress leading to apoptosis and inhibition of tumor growth in Neuroblastoma

“…The dose‐dependent increase in ROS positively correlates with cell death among NB cells when treated with Tolcapone, providing support for ROS production as one mechanism by which Tolcapone is toxic to NB cells. Previous studies have also seen that sharp increases in ROS induce apoptosis in cancers other than NB .…”

TRAIL Enhances Shikonin Induced Apoptosis through ROS/JNK Signaling in Cholangiocarcinoma Cells

“…Diaporine induced the apoptosis of breast cancer cells through increasing ROS release [41]. In prostate cancer, hydroxychavicol-induced ROS triggered mitochondrially-mediated intrinsic apoptosis [42]. Zhong et al demonstrated that guggulsterone-induced apoptosis of CCA cells was achieved by ROS mediated JNK signaling pathway in CCA [26].…”