2. Academic Validation
  3. Luteolin exhibits synergistic therapeutic efficacy with erastin to induce ferroptosis in colon cancer cells through the HIC1-mediated inhibition of GPX4 expression

Luteolin exhibits synergistic therapeutic efficacy with erastin to induce ferroptosis in colon cancer cells through the HIC1-mediated inhibition of GPX4 expression

  • Free Radic Biol Med. 2023 Sep 15;S0891-5849(23)00638-X. doi: 10.1016/j.freeradbiomed.2023.09.014.
Yinli Zheng 1,  Leyan Li 2,  Haipeng Chen 3,  Yuting Zheng 4,  Xuanjing Tan 5,  Guiyu Zhang 6,  Ruidi Jiang 7,  Hong Yu 8,  Senyi Lin 9,  Yijie Wei 10,  Ying Wang 11,  Rong Zhang 12,  Zhongqiu Liu 13,  Jinjun Wu 14
Affiliations

Affiliations

  • 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China. Electronic address: zhengyinl@sysucc.org.cn.
  • 2 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: 13450776765@139.com.
  • 3 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: C1251343392@163.com.
  • 4 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: 13642455322@163.com.
  • 5 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: txjrabbit@163.com.
  • 6 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: zhangguiyu@gzucm.edu.cn.
  • 7 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: ruidi2001@126.com.
  • 8 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: 15310505297@163.com.
  • 9 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: gzucm2021027043@163.com.
  • 10 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: weiyj2002@163.com.
  • 11 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: wangy@gzucm.edu.cn.
  • 12 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: zhangrong@gzucm.edu.cn.
  • 13 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: liuzq@gzucm.edu.cn.
  • 14 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, PR China. Electronic address: wujinjun@gzucm.edu.cn.
PMID: 37717793 DOI: 10.1016/j.freeradbiomed.2023.09.014
Abstract

Colon Cancer continues to be a prevalent gastrointestinal malignancy with a bleak prognosis. The induction of Ferroptosis, a new form of regulated cell death, has emerged as a potentially effective strategy for the treatment of colon Cancer. However, numerous colon Cancer cells display resistance to Ferroptosis induced by erastin, a well-established Ferroptosis inducer. Finding drugs that can enhance the susceptibility of colon Cancer cells to erastin is of utmost importance. This study aimed to examine the synergistic therapeutic impact of combining erastin with a bioactive flavonoid compound luteolin on the ferroptosis-mediated suppression of colon Cancer. Human colon Cancer HCT116 and SW480 cells were used for the in vitro studies and a xenograft of colon Cancer model in BALB/c nude mice was established for the in vivo experiments. The results showed that combinative treatment of luteolin and erastin effectively inhibited the viability and proliferation of colon Cancer cells. Luteolin and erastin cotreatment synergistically induced Ferroptosis, concomitant with a reduction in glutathione and an elevation in lipid peroxides. In vivo, combinative treatment of luteolin and erastin exhibited a pronounced therapeutic effect on xenografts of colon Cancer, characterized by a significant induction of Ferroptosis. Mechanistically, luteolin in combination with erastin synergistically reduced the expression of Glutathione Peroxidase 4 (GPX4), an antioxidase overexpressed in colon Cancer cells. Furthermore, luteolin and erastin cotreatment significantly upregulated the expression of hypermethylated in Cancer 1 gene (HIC1), a transcriptional repressor also recognized as a tumor suppressor. HIC1 overexpression notably augmented the suppression of GPX4 expression and facilitated ferroptotic cell death. In contrast, HIC1 silencing attenuated the inhibition of GPX4 expression and eliminated the Ferroptosis. Conclusively, these results clearly demonstrated that luteolin acts synergistically with erastin and renders colon Cancer cells vulnerable to Ferroptosis through the HIC1-mediated inhibition of GPX4 expression, which may act as a promising therapeutic strategy.

Keywords

Colon cancer; Erastin; Ferroptosis; GPX4; HIC1; Luteolin.

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