Lycorine Hydrochloride Inhibits Cell Proliferation and Induces Apoptosis Through Promoting FBXW7-MCL1 Axis in Gastric Cancer

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2020 Oct 31

PMID 33126914

Citations 40

Authors

Chongyang Li

Chaowei Deng

Guangzhao Pan

Xue Wang

Kui Zhang

Zhen Dong

Gaichao Zhao

Mengqin Tan

Xiaosong Hu

Shaomin Shi

Juan Du

Haoyan Ji

Xiaowen Wang

Liqun Yang

Hongjuan Cui

Affiliations

Soon will be listed here.

Abstract

Background: Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment.

Methods: The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry).

Results: In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14-1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer.

Conclusions: The efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumor compound for gastric cancer.

Citing Articles

Suppresses the Proliferation and Invasion of Esophageal Cancer by Targeting TRIM22 and Inhibiting the JAK2/STAT3 and Erk Pathways.

Liu J, Qiu L, Chen J, Zeng T Cancers (Basel). 2025; 17(5).

PMID: 40075566 PMC: 11898953. DOI: 10.3390/cancers17050718.

Disulfidptosis classification of pancreatic carcinoma reveals correlation with clinical prognosis and immune profile.

Shi J, Zhao L, Wang K, Lin J, Shen J Hereditas. 2025; 162(1):26.

PMID: 39987145 PMC: 11846472. DOI: 10.1186/s41065-025-00381-z.

FBXW7 in gastrointestinal cancers: from molecular mechanisms to therapeutic prospects.

Wang W, Liu X, Zhao L, Jiang K, Yu Z, Yang R Front Pharmacol. 2025; 15:1505027.

PMID: 39749199 PMC: 11694028. DOI: 10.3389/fphar.2024.1505027.

Pan-Cancer Analysis of the Prognostic and Immunological Role of SEMA7A.

Yang L, Zhang S, Zheng L, Kong F, Dang W, Shen S Int J Gen Med. 2024; 17:6443-6461.

PMID: 39735166 PMC: 11682669. DOI: 10.2147/IJGM.S499872.

HER-2 Receptor and αvβ3 Integrin Dual-Ligand Surface-Functionalized Liposome for Metastatic Breast Cancer Therapy.

Arya D, Deshpande H, Kumar A, Chidambaram K, Pandey P, Anjum S Pharmaceutics. 2024; 16(9).

PMID: 39339166 PMC: 11435421. DOI: 10.3390/pharmaceutics16091128.

References

Zhao Y, Zhang J, Cheng A, Yu J, To K, Kang W . Gastric cancer: genome damaged by bugs. Oncogene. 2020; 39(17):3427-3442. PMC: 7176583. DOI: 10.1038/s41388-020-1241-4. View

Li W, Zhang X, Wu F, Zhou Y, Bao Z, Li H . Gastric cancer-derived mesenchymal stromal cells trigger M2 macrophage polarization that promotes metastasis and EMT in gastric cancer. Cell Death Dis. 2019; 10(12):918. PMC: 6892854. DOI: 10.1038/s41419-019-2131-y. View

Montagnani F, Crivelli F, Aprile G, Vivaldi C, Pecora I, De Vivo R . Long-term survival after liver metastasectomy in gastric cancer: Systematic review and meta-analysis of prognostic factors. Cancer Treat Rev. 2018; 69:11-20. DOI: 10.1016/j.ctrv.2018.05.010. View

Kitayama J, Ishigami H, Yamaguchi H, Sakuma Y, Horie H, Hosoya Y . Treatment of patients with peritoneal metastases from gastric cancer. Ann Gastroenterol Surg. 2018; 2(2):116-123. PMC: 5881364. DOI: 10.1002/ags3.12060. View

Song Y, Wang Y, Tong C, Xi H, Zhao X, Wang Y . A unified model of the hierarchical and stochastic theories of gastric cancer. Br J Cancer. 2017; 116(8):973-989. PMC: 5396111. DOI: 10.1038/bjc.2017.54. View

Jakubek M, Kejik Z, Kaplanek R, Hromadka R, Sandrikova V, Sykora D . Strategy for improved therapeutic efficiency of curcumin in the treatment of gastric cancer. Biomed Pharmacother. 2019; 118:109278. DOI: 10.1016/j.biopha.2019.109278. View

Wu Q, Yang Z, Nie Y, Shi Y, Fan D . Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett. 2014; 347(2):159-66. DOI: 10.1016/j.canlet.2014.03.013. View

Wang J, Du J, Zhang Y, Zhao X, Fan R, Wang Z . Dynamic changes and surveillance function of prion protein expression in gastric cancer drug resistance. World J Gastroenterol. 2011; 17(35):3986-93. PMC: 3199556. DOI: 10.3748/wjg.v17.i35.3986. View

Leist M, Jaattela M . Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol. 2001; 2(8):589-98. DOI: 10.1038/35085008. View

10.

Kaufmann S, Gores G . Apoptosis in cancer: cause and cure. Bioessays. 2000; 22(11):1007-17. DOI: 10.1002/1521-1878(200011)22:11<1007::AID-BIES7>3.0.CO;2-4. View

11.

Johnstone R, Ruefli A, Lowe S . Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002; 108(2):153-64. DOI: 10.1016/s0092-8674(02)00625-6. View

12.

Park H, Cho S, Kim H, Na D, Han J, Chae J . Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer. Proc Natl Acad Sci U S A. 2015; 112(40):12492-7. PMC: 4603466. DOI: 10.1073/pnas.1507491112. View

13.

Youle R, Strasser A . The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2007; 9(1):47-59. DOI: 10.1038/nrm2308. View

14.

Adams J, Cory S . The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007; 26(9):1324-37. PMC: 2930981. DOI: 10.1038/sj.onc.1210220. View

15.

Belmar J, Fesik S . Small molecule Mcl-1 inhibitors for the treatment of cancer. Pharmacol Ther. 2014; 145:76-84. PMC: 4340597. DOI: 10.1016/j.pharmthera.2014.08.003. View

16.

Chen L, Willis S, Wei A, Smith B, Fletcher J, Hinds M . Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005; 17(3):393-403. DOI: 10.1016/j.molcel.2004.12.030. View

17.

Ashkenazi A, Fairbrother W, Leverson J, Souers A . From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 2017; 16(4):273-284. DOI: 10.1038/nrd.2016.253. View

18.

Tse C, Shoemaker A, Adickes J, Anderson M, Chen J, Jin S . ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008; 68(9):3421-8. DOI: 10.1158/0008-5472.CAN-07-5836. View

19.

Zhao Y, He J, Li J, Peng X, Wang X, Dong Z . Demethylzeylasteral inhibits cell proliferation and induces apoptosis through suppressing MCL1 in melanoma cells. Cell Death Dis. 2017; 8(10):e3133. PMC: 5682691. DOI: 10.1038/cddis.2017.529. View

20.

Shoemaker A, Mitten M, Adickes J, Ackler S, Refici M, Ferguson D . Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res. 2008; 14(11):3268-77. DOI: 10.1158/1078-0432.CCR-07-4622. View