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

Pharmaceutical Science Advances Pub Date : 2024-11-10 DOI:10.1016/j.pscia.2024.100057

Pengfei Shang , Jiawei Yang , Lijun Shao , Chao Sun , Jianbo Ji , Xiaoyan Wang , Zongxue Zheng , Xiuli Guo

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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.

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槲皮素通过抑制 ROS 和 PI3K/AKT 通路抑制缺氧条件下高转移性晚期结肠癌的恶性进展

晚期转移性结肠癌难以用现有的化疗药物治疗，而缺氧微环境与结肠癌的血管生成和远处转移密切相关。槲皮素是一种天然黄酮类化合物，具有抗肿瘤作用。本研究旨在探讨槲皮素单独或与 5-FU 联用对缺氧环境下晚期转移性或原发性结直肠癌的侵袭和转移的影响。采用 CCK8 检测法、Hoechst 33342、流式细胞术和 AO 染色法检测槲皮素或/和 5-FU 对结肠癌细胞的细胞毒性。槲皮素或/和5-FU对迁移和侵袭的影响通过transwell、细胞划痕法和小鼠异种移植模型进行了测定。通过 Western 印迹和免疫荧光检测探讨了其潜在机制。结果显示，槲皮素通过抑制ROS、HIF-1α和PI3K/AKT通路的表达，有效抑制了高转移晚期结肠癌LOVO细胞在缺氧条件下的侵袭和迁移。槲皮素与5-FU联用可促进5-FU对LOVO细胞侵袭和迁移的抑制作用。此外，槲皮素还能通过诱导细胞凋亡和自噬，显著抑制缺氧条件下LOVO细胞或HT-29细胞的增殖，尤其是对HT-29细胞的抑制作用强于LOVO细胞。总之，槲皮素通过抑制ROS和HIF-1α的表达以及下调PI3K/AKT通路，抑制了低氧条件下晚期转移性结肠癌LOVO细胞的侵袭和迁移。此外，槲皮素单独或与 5-FU 联用可有效抑制高转移性晚期结肠癌的侵袭和迁移。槲皮素有望作为一种有效的抗结肠癌药物单独或联合用于晚期结肠癌的临床治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Pharmaceutical Science Advances

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