Inhibition of AP-1 and MAPK signaling and activation of Nrf2/ARE pathway by quercitrin

Abstract

Abstract. Quercitrin, glycosylated form of flavonoid compounds, is widely distributed in nature. Extensive studies have demonstrated that quercitrin exhibits strong antioxidant and anti-carcinogenic activities. However, the molecular mechanism is poorly understood. The present study examines the effects of quercitrin on tumor promotion in mouse JB6 cells, a validated model for screening cancer chemopreventive agents and elucidating the molecular mechanisms. Quercitrin blocked TPA-induced neoplastic transformation in JB6 P + cells. Pretreatment of JB6 cells with quercitrin down-regulated transactivation of AP-1 and NF-κB induced by UVB or TPA. In the skin of AP-1-luciferase transgenic mice, topical treatment of the mouse with quercitrin markedly blocked the TPA-induced AP-1 transactivation. Further studies indicated that these inhibitory actions appear to be mediated through the inhibition of MAPKs phosphorylation, including ERKs, p38 kinase, and JNKs. In addition, quercitrin stimulated the activation of NF-E2-related factor (Nrf2) and GST AREluciferase activity. Comet assays showed that quercitrin could block DNA damage induced by UVB. To our knowledge, these results provide the first evidence that quercitrin contributes to the inhibition of neoplastic transformation by blocking activation of the MAPK pathway and stimulation of cellular protection signaling. Moreover, to our knowledge, these findings provide the first molecular basis for the anticarcinogenic action of quercitrin. IntroductionPrevious studies have indicated that reactive oxidative species (ROS) function as second messengers in numerous signaling pathways involved in a diverse array of biological responses ranging from transcriptional regulation, differentiation and proliferation to oncogenic transformation (1,2). Increased formation of ROS can promote the development of malignancy, and the 'normal' rates of ROS generation may account for the increased risk of cancer development and neurodegenerative disorders (3,4). Therefore, interventions favoring the scavenging of ROS (dietary and pharmacological antioxidants) to attenuate the oxidative stress may prevent oxidant stressassociated diseases. A report published by the American Institute for Cancer Research regarding dietary prevention of cancer indicates that 7-31% of all cancers worldwide could be reduced by diets high in fruits and vegetables (5). Thus, searching for novel natural agents and defining novel targets for chemoprevention have become an important area of investigation.Flavonoids are components of the human diet and are widely found in vegetables and fruits (4). Flavonoids exert various biological activities, which are mainly related to their abilities to inhibit enzymes, to their antioxidant properties, and to their effects on immune responses (6). These activities may explain the beneficial effects that flavonoid intake exerts in different human pathologies, including hypertension, inflammatory conditions, and cancer (7). Quercetin is the most abundant bioflavonoid compound, which ...

Molecular Mechanisms of Quercitrin-induced Apoptosis in Non-small Cell Lung Cancer

“…Xu et al studied the molecular mechanisms of apoptosis in prostate cancer induced by quercitrin and found that quercitrin exerted little effect and was not effective at inducing apoptosis (20). Ding et al examined the effects of quercitrin on tumor promotion in mouse JB6 cells and quercitrin blocked TPA-induced neoplastic transformation in JB6 Pþ cells (14). They also showed that quercitrin stimulated the activation of NF-E2-related factor (Nrf2) and GST ARE luciferase activity and that it was able to block DNA damage induced by UVB (14).…”

“…Ding et al examined the effects of quercitrin on tumor promotion in mouse JB6 cells and quercitrin blocked TPA-induced neoplastic transformation in JB6 Pþ cells (14). They also showed that quercitrin stimulated the activation of NF-E2-related factor (Nrf2) and GST ARE luciferase activity and that it was able to block DNA damage induced by UVB (14).…”

“…These properties could explain the beneficial effects that flavonoid intake exerts in different human pathologies including hypertension, inflammatory conditions, and cancer (13). Quercitrin is the most abundant bioflavonoid compound, which is mainly present in the glycoside form (14). The sugar portion is bound to the aglycone portion in quercitrin that increases its solubility and improves absorption.…”

Apoptotic Effects of Quercitrin on DLD-1 Colon Cancer Cell Line

“…Ding et al examined the effects of quercitrin on neoplastic JB6 cells, the results demonstrated that the TPAinduced neoplastic transformation is blocked in tumor cells. They also showed that quercitrin stimulated the activation of NF-E2-related factor (Nrf2), which is essential in the regulation of cellular protective genes, and blocked damage in DNA due to UVB [13].…”

“…These properties could explain the beneficial effects of these natural molecules that have already been used in hypertension, inflammation, and cancer treatments [12]. Quercetin in the glycoside form is the most abundant bioflavonoid compound [13]. Quercitrin is a flavonoid with antinflammatory activity in experimental colitis, associated with an antioxidative action [14].…”