Huaier extract dose-dependently promotes ferroptosis pathway and inhibits biological behavior in colorectal cancer cells SW620_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

JIA Yifan ¹ , DENG Wenhong ^1,2 , QIU Zhendong ^1,2 ,  XU Sheng ³

1. Renmin Hospital of Wuhan University, Wuhan 430060, P. R. China;
2. Key Laboratory of Hubei Province for Digestive System Disease, Wuhan 430060, P. R. China;
3. Department of General Surgery, Renmin Hospital of Guangxi Zhuang Autonomous Region, Nanning 530016, P. R. China;

Corresponding author：

XU Sheng, Email: 651325828@qq.com

Keywords：

natural medicine; Huaier; ferroptosis; colorectal cancer; cell

DOI：

10.7507/1007-9424.202208064

Video：

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Objective To investigate the effect of Huaier extract on the proliferation, invasion, and ferroptosis pathways of colorectal cancer (CRC) cells. Methods The CRC cell line SW620 was cultured in vitro, and the cells were treated with Huaier extract solution at different concentrations (0, 5, 10, 20, and 50 mg/mL). The cell counting kit 8 was used to detect the proliferation of CRC cells at different concentrations to scree the test dose of the Huaier extract. The Transwell and the scratch assays were used to detect the cell invasion and migration. The reactive oxygen species (ROS), glutathione (GSH), and malondialdehyde (MDA) kits were used to detect the cellular oxidative stress level. The Western blot was used to detect the ferroptosis-related proteins levels, including glutathione peroxidase 4 (GPX4), nuclear factor E2-related factor 2 (NRF2), and high mobility group box-1 (HMGB1). Results In this study, it could statistically inhibit the proliferation of CRC cells after 48 h interfering with Huaier extract at 10, 20 mg/mL concentrations, so we chose 10, 20 mg/mL concentrations as the test dose, 0 mg/L as the control dose. Huaier extract effectively inhibited the migration and invasion abilities of SW620 cells in a dose-dependent manner (Transwell: F=480.0, P<0.001; scratch assay: F=24.3, P=0.001). The level of ROS in the SW620 cells increased with the increase of concentration in a dose-dependent manner (F=806.3, P<0.001). the level of GSH in the SW620 cells decreased with the increase of concentration in a dose-dependent manner (F=35.0, P=0.005), but the level of MDA was highest at 10 mg/mL (F=22.9, P=0.002) . Further the Huaier extract could effectively reduce the expressions of GPX4 (F=74.2, P<0.001), NRF2 (F=32.8, P=0.001), and HMGB1 (F=55.1, P<0.001) in a dose-dependent manner. Conclusion From the results of this study, Huaier extract at 10 and 20 mg/mL concentrations can inhibit the proliferation and invasion of CRC SW620 cells by inducing ferroptosis.

Citation： JIA Yifan, DENG Wenhong, QIU Zhendong, XU Sheng. Huaier extract dose-dependently promotes ferroptosis pathway and inhibits biological behavior in colorectal cancer cells SW620. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(2): 185-191. doi: 10.7507/1007-9424.202208064 Copy

1.	Qi T, Dong Y, Gao Z, et al. Research progress on the anti-cancer molecular mechanisms of Huaier. Onco Targets Ther, 2020, 13: 12587-12599.
2.	Xu DQ, Yuan XJ, Toyoda H, et al. Anti-tumor effect of Huaier extract against neuroblastoma cells in vitro. Int J Med Sci, 2021, 18(4): 1015-1023.
3.	Ji D, Zheng W, Huang P, et al. Huaier restrains cholangiocarcinoma progression in vitro and in vivo through modulating lncRNA TP73-AS1 and inducing oxidative stress. Onco Targets Ther, 2020, 13: 7819-7837.
4.	Luo Z, Hu X, Xiong H, et al. A polysaccharide from Huaier induced apoptosis in MCF-7 breast cancer cells via down-regulation of MTDH protein. Carbohydr Polym, 2016, 151: 1027-1033.
5.	Hu Z, Yang A, Fan H, et al. Huaier aqueous extract sensitizes cells to rapamycin and cisplatin through activating mTOR signaling. J Ethnopharmacol, 2016, 186: 143-150.
6.	Fang L, Zhang Y, Zang Y, et al. HP-1 inhibits the progression of ccRCC and enhances sunitinib therapeutic effects by suppressing EMT. Carbohydr Polym, 2019, 223: 115109. doi: 10.1016/j.carbpol.2019.115109.
7.	Chen Y, Wu H, Wang X, et al. Huaier granule extract inhibit the proliferation and metastasis of lung cancer cells through down-regulation of MTDH, JAK2/STAT3 and MAPK signaling pathways. Biomed Pharmacother, 2018, 101: 311-321.
8.	Hu B, Yan W, Wang M, et al. Huaier polysaccharide inhibits the stem-like characteristics of ERα-36 high triple negative breast cancer cells via inactivation of the ERα-36 signaling pathway. Int J Biol Sci, 2019, 15(7): 1358-1367.
9.	Liu Z, Liu C, Yan K, et al. Huaier extract inhibits prostate cancer growth via targeting AR/AR-V7 pathway. Front Oncol, 2021, 11: 615568. doi: 10.3389/fonc.2021.615568.
10.	Su D, Jiang B, Yang Y, et al. Effect of Huaier on melanoma invasion, metastasis, and angiogenesis. Biomed Res Int, 2020, 2020: 8163839. doi: 10.1155/2020/8163839.
11.	Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282.
12.	Chen P, Wu Q, Feng J, et al. Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis. Signal Transduct Target Ther, 2020, 5(1): 51. doi: 10.1038/s41392-020-0149-3.
13.	Chen P, Li X, Zhang R, et al. Combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transformation. Theranostics, 2020, 10(11): 5107-5119.
14.	Pooja T, Karunagaran D. Emodin suppresses Wnt signaling in human colorectal cancer cells SW480 and SW620. Eur J Pharmacol, 2014, 742: 55-64.
15.	Hanušová V, Skálová L, Králová V, et al. The effect of flubendazole on adhesion and migration in SW480 and SW620 colon cancer cells. Anticancer Agents Med Chem, 2018, 18(6): 837-846.
16.	Wang L, Xu L, Wang Y. Huaier inhibits proliferation, migration, and invasion of cutaneous squamous cell carcinoma cells by inhibiting the methylation levels of CDKN2A and TP53. Integr Cancer Ther, 2021, 20: 15347354211031646. doi: 10.1177/15347354211031646.
17.	Wang Y, Lv H, Xu Z, et al. Huaier n-butanol extract suppresses proliferation and metastasis of gastric cancer via c-Myc-Bmi1 axis. Sci Rep, 2019, 9(1): 447. doi: 10.1038/s41598-018-36940-w.
18.	Zhang Y, Lou Y, Wang J, et al. Research status and molecular mechanism of the traditional Chinese medicine and antitumor therapy combined strategy based on tumor microenvironment. Front Immunol, 2021, 11: 609705. doi: 10.3389/fimmu.2020.609705.
19.	Frampton D, Schwenzer H, Marino G, et al. Molecular signatures of regression of the canine transmissible venereal tumor. Cancer Cell, 2018, 33(4): 620-633.
20.	Zierhut C, Yamaguchi N, Paredes M, et al. The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell, 2019, 178(2): 302-315.
21.	Zhou Q, Shao S, Wang J, et al. Enzyme-activatable polymer-drug conjugate augments tumour penetration and treatment efficacy. Nat Nanotechnol, 2019, 14(8): 799-809.
22.	Zou YF, Rong YM, Chen ZX, et al. Effects of Huaier extract on ameliorating colitis-associated colorectal tumorigenesis in mice. Onco Targets Ther, 2020, 13: 8691-8704.
23.	Wang Z, Yu XL, Zhang J, et al. Huaier granule prevents the recurrence of early-stage hepatocellular carcinoma after thermal ablation: a cohort study. J Ethnopharmacol, 2021, 281: 114539. doi: 10.1016/j.jep.2021.114539.
24.	Zhang T, Wang K, Zhang J, et al. Huaier aqueous extract inhibits colorectal cancer stem cell growth partially via downregulation of the Wnt/β-catenin pathway. Oncol Lett, 2013, 5(4): 1171-1176.
25.	邹一丰, 刘华山, 戎煜明, 等. 槐耳清膏对结直肠癌细胞增殖和侵袭能力的影响. 消化肿瘤杂志(电子版), 2019, 11(4): 336-340.
26.	谢海娟, 王毓兴, 张丽君, 等. 槐耳浸膏通过调控ROS抑制结直肠癌细胞MMP-9表达及侵袭能力的研究. 中国中西医结合消化杂志, 2021, 29(5): 336-341.
27.	Xu DQ, Yuan XJ, Hirayama M, et al. Huaier extract induces apoptosis in hepatoblastoma cells via the MEK/ERK signaling pathway. In Vivo, 2020, 34(5): 2381-2388.
28.	Xie J, Zhuan B, Wang H, et al. Huaier extract suppresses non-small cell lung cancer progression through activating NLRP3-dependent pyroptosis. Anat Rec (Hoboken), 2021, 304(2): 291-301.
29.	朱晨, 张程亮, 杨金玉, 等. 槐耳颗粒缓解奥沙利铂诱导肝脏损伤的作用及机制研究. 中国医院药学杂志, 2021, 41(17): 1723-1729.
30.	Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell, 2018, 34(1): 21-43.
31.	Chen X, Yu C, Kang R, et al. Cellular degradation systems in ferroptosis. Cell Death Differ, 2021, 28(4): 1135-1148.

1. Qi T, Dong Y, Gao Z, et al. Research progress on the anti-cancer molecular mechanisms of Huaier. Onco Targets Ther, 2020, 13: 12587-12599.
2. Xu DQ, Yuan XJ, Toyoda H, et al. Anti-tumor effect of Huaier extract against neuroblastoma cells in vitro. Int J Med Sci, 2021, 18(4): 1015-1023.
3. Ji D, Zheng W, Huang P, et al. Huaier restrains cholangiocarcinoma progression in vitro and in vivo through modulating lncRNA TP73-AS1 and inducing oxidative stress. Onco Targets Ther, 2020, 13: 7819-7837.
4. Luo Z, Hu X, Xiong H, et al. A polysaccharide from Huaier induced apoptosis in MCF-7 breast cancer cells via down-regulation of MTDH protein. Carbohydr Polym, 2016, 151: 1027-1033.
5. Hu Z, Yang A, Fan H, et al. Huaier aqueous extract sensitizes cells to rapamycin and cisplatin through activating mTOR signaling. J Ethnopharmacol, 2016, 186: 143-150.
6. Fang L, Zhang Y, Zang Y, et al. HP-1 inhibits the progression of ccRCC and enhances sunitinib therapeutic effects by suppressing EMT. Carbohydr Polym, 2019, 223: 115109. doi: 10.1016/j.carbpol.2019.115109.
7. Chen Y, Wu H, Wang X, et al. Huaier granule extract inhibit the proliferation and metastasis of lung cancer cells through down-regulation of MTDH, JAK2/STAT3 and MAPK signaling pathways. Biomed Pharmacother, 2018, 101: 311-321.
8. Hu B, Yan W, Wang M, et al. Huaier polysaccharide inhibits the stem-like characteristics of ERα-36 high triple negative breast cancer cells via inactivation of the ERα-36 signaling pathway. Int J Biol Sci, 2019, 15(7): 1358-1367.
9. Liu Z, Liu C, Yan K, et al. Huaier extract inhibits prostate cancer growth via targeting AR/AR-V7 pathway. Front Oncol, 2021, 11: 615568. doi: 10.3389/fonc.2021.615568.
10. Su D, Jiang B, Yang Y, et al. Effect of Huaier on melanoma invasion, metastasis, and angiogenesis. Biomed Res Int, 2020, 2020: 8163839. doi: 10.1155/2020/8163839.
11. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282.
12. Chen P, Wu Q, Feng J, et al. Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis. Signal Transduct Target Ther, 2020, 5(1): 51. doi: 10.1038/s41392-020-0149-3.
13. Chen P, Li X, Zhang R, et al. Combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transformation. Theranostics, 2020, 10(11): 5107-5119.
14. Pooja T, Karunagaran D. Emodin suppresses Wnt signaling in human colorectal cancer cells SW480 and SW620. Eur J Pharmacol, 2014, 742: 55-64.
15. Hanušová V, Skálová L, Králová V, et al. The effect of flubendazole on adhesion and migration in SW480 and SW620 colon cancer cells. Anticancer Agents Med Chem, 2018, 18(6): 837-846.
16. Wang L, Xu L, Wang Y. Huaier inhibits proliferation, migration, and invasion of cutaneous squamous cell carcinoma cells by inhibiting the methylation levels of CDKN2A and TP53. Integr Cancer Ther, 2021, 20: 15347354211031646. doi: 10.1177/15347354211031646.
17. Wang Y, Lv H, Xu Z, et al. Huaier n-butanol extract suppresses proliferation and metastasis of gastric cancer via c-Myc-Bmi1 axis. Sci Rep, 2019, 9(1): 447. doi: 10.1038/s41598-018-36940-w.
18. Zhang Y, Lou Y, Wang J, et al. Research status and molecular mechanism of the traditional Chinese medicine and antitumor therapy combined strategy based on tumor microenvironment. Front Immunol, 2021, 11: 609705. doi: 10.3389/fimmu.2020.609705.
19. Frampton D, Schwenzer H, Marino G, et al. Molecular signatures of regression of the canine transmissible venereal tumor. Cancer Cell, 2018, 33(4): 620-633.
20. Zierhut C, Yamaguchi N, Paredes M, et al. The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell, 2019, 178(2): 302-315.
21. Zhou Q, Shao S, Wang J, et al. Enzyme-activatable polymer-drug conjugate augments tumour penetration and treatment efficacy. Nat Nanotechnol, 2019, 14(8): 799-809.
22. Zou YF, Rong YM, Chen ZX, et al. Effects of Huaier extract on ameliorating colitis-associated colorectal tumorigenesis in mice. Onco Targets Ther, 2020, 13: 8691-8704.
23. Wang Z, Yu XL, Zhang J, et al. Huaier granule prevents the recurrence of early-stage hepatocellular carcinoma after thermal ablation: a cohort study. J Ethnopharmacol, 2021, 281: 114539. doi: 10.1016/j.jep.2021.114539.
24. Zhang T, Wang K, Zhang J, et al. Huaier aqueous extract inhibits colorectal cancer stem cell growth partially via downregulation of the Wnt/β-catenin pathway. Oncol Lett, 2013, 5(4): 1171-1176.
25. 邹一丰, 刘华山, 戎煜明, 等. 槐耳清膏对结直肠癌细胞增殖和侵袭能力的影响. 消化肿瘤杂志(电子版), 2019, 11(4): 336-340.
26. 谢海娟, 王毓兴, 张丽君, 等. 槐耳浸膏通过调控ROS抑制结直肠癌细胞MMP-9表达及侵袭能力的研究. 中国中西医结合消化杂志, 2021, 29(5): 336-341.
27. Xu DQ, Yuan XJ, Hirayama M, et al. Huaier extract induces apoptosis in hepatoblastoma cells via the MEK/ERK signaling pathway. In Vivo, 2020, 34(5): 2381-2388.
28. Xie J, Zhuan B, Wang H, et al. Huaier extract suppresses non-small cell lung cancer progression through activating NLRP3-dependent pyroptosis. Anat Rec (Hoboken), 2021, 304(2): 291-301.
29. 朱晨, 张程亮, 杨金玉, 等. 槐耳颗粒缓解奥沙利铂诱导肝脏损伤的作用及机制研究. 中国医院药学杂志, 2021, 41(17): 1723-1729.
30. Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell, 2018, 34(1): 21-43.
31. Chen X, Yu C, Kang R, et al. Cellular degradation systems in ferroptosis. Cell Death Differ, 2021, 28(4): 1135-1148.

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Huaier extract dose-dependently promotes ferroptosis pathway and inhibits biological behavior in colorectal cancer cells SW620

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