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

Abstract

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.

Keywords

Quercetin / Colon cancer / Hypoxia / PI3K/AKT pathway

CRediT authorship contribution statement

Pengfei Shang: Writing - original draft, Validation, Investigation, Data curation, Conceptualization. Jiawei Yang: Writing - original draft, Visualization, Investigation, Data curation, Conceptualization. Lijun Shao: Writing - review & editing, Data curation. Chao Sun: Investigation. Jianbo Ji: Investigation. Xiaoyan Wang: Investigation. Zongxue Zheng: Investigation. Xiuli Guo: Writing - review & editing, Writing - original draft, Supervision, Conceptualization.

Availability of data and material

The data are available upon request.

Ethics approval

The experiment protocols were performed following the regulation of Welfare Committee and the Animal Care of Shandong University with affidavit of approval of animal ethical and welfare (Approval No. 18004).

Funding information

This work was supported by Special funds for local scientific and technological development of Shandong Province guided by the central government [YDZX2021023] and National Science Foundation of China Grants [82173843].

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Not applicable.

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