Inhibitory effects of Pericarpium Citri Reticulatae ‘Chachi’ flavonoid extracts during storage against NSCLC in vivo and in vitro

Pericarpium Citri Reticulatae ‘Chachi’ (PCR-C), rich in flavonoids, shows antioxidative, anti-inflammatory, and antitumor effects, which was traditionally considered to be “the longer periods, the better”. The bioactivity of flavonoids depends on gastrointestinal absorption and hepatic metabolism. This work aims to investigate which metabolites of flavonoids are the differential factors that mainly contributed to the variance of inhibitory effect of PCR-C flavonoid extracts (PCR-CF) against non-small cell lung cancer (NSCLC) during storage. The inhibitory effect of PCR-CF against NSCLC was evaluated by subcutaneous xenograft tumor model and Caco-2/HepG2 coculture model. Non-targeted metabolomics was employed to analyze the metabolic difference of PCR-CF during storage. Results showed that PCR-CF during storage inhibited tumor growth in vivo . Meanwhile, PCR-CF during storage inhibited A549 cell proliferation and induced cell apoptosis and cell cycle arrest at G2/M phase via ROS-dependent generation involving in MAPK pathway in vitro . Furthermore, 15 flavonoids metabolites were identified as marker differential metabolites affecting the variance of inhibitory effect of PCR-CF during storage against NSCLC. This study indicated that the inhibitory effects of PCR-CF against NSCLC were improved with the extended storage periods due to the variance of differential metabolites. The results would provide scientific guidance for quality control of PCR-C during storage.

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