Quercetin inhibits malignant progression of high metastatic advanced colon cancer in hypoxia via suppressing ROS and PI3K/AKT pathway

Advanced metastatic colon cancer is difficult to treat with existing chemotherapy medicines, and hypoxic microenvironment is closely related to angiogenesis and distant metastasis of colon cancer. Quercetin, a natural flavonoid, has been shown anti-tumor effects. The aim of this study is to investigate the effect of quercetin alone or combined with 5-FU on the invasion and metastasis of advanced metastatic or primary colorectal cancer in hypoxic environment. The cytotoxicity of quercetin or/and 5-FU on colon cancer cells using CCK8 assay, Hoechst 33342, flow cytometry and AO staining. The effects of quercetin or/and 5-FU on the migration and invasion were determined by transwell, cell scratching method and murine xenograft models. The potential mechanism was explored by Western blot and immunofluorescent assay. The results revealed quercetin effectively inhibited the invasion and migration of high metastatic advanced colon cancer LOVO cells under hypoxia through the inhibition of ROS and the expression of HIF-1α and PI3K/AKT pathway. Combination of quercetin and 5-FU could promote the inhibition of 5-FU on the invasion and migration of LOVO cells. Moreover, quercetin also significantly inhibited the proliferation of either LOVO cells or HT-29 ​cells under hypoxia by inducing apoptosis and autophagy, particularly, showing stronger inhibition on HT-29 ​cells than LOVO cells. In conclusion, quercetin inhibited the invasion and migration of advanced metastatic colon cancer LOVO cells under hypoxia through inhibition of ROS and HIF-1α expression and the downregulation of PI3K/AKT pathway. Moreover, quercetin alone or in combination with 5-FU can effectively inhibit the invasion and migration of high metastatic advanced colon cancer. Quercetin has the potential to be used as an effective anti-colon cancer drug alone or in combination for the clinical treatment of advanced colon cancer.