Artesunate Promotes Cervical Cancer Cell Apoptosis by Regulating Bcl2 Family Molecules and Reducing the Mitochondrial Membrane Potential

Overview

Journal Oncol Lett

Specialty Oncology

Date 2024 May 29

PMID 38807670

Authors

Qianying Zhang

Xing Li

Caiyi He

Rongmiao Zhou

Jing Wang

Liang Liu

Affiliations

Soon will be listed here.

Abstract

Artesunate (ART), an antimalarial drug, has a broad spectrum of antitumour effects in cancer types such as esophageal and gastric cancer. However, evidence demonstrating the role of ART in cervical cancer cells is limited. In the present study, the inhibitory effect of ART on the growth of cervical cancer cells through the modulation of the cell cycle and apoptosis was investigated. The growth-inhibitory effect of ART on a cervical cancer cell line (SiHa) was detected using a Cell Counting Kit-8 assay after treatment with ART for 24 h, after which the half-maximal inhibitory concentration (IC) was calculated. Using flow cytometry assays, apoptosis, the cell cycle, the levels of reactive oxygen species (ROS) and calcium (Ca) ions, as well as the mitochondrial membrane potential were evaluated in SiHa cells following treatment with ART for 24 and 48 h. The mRNA expression levels of Bcl2, Bcl-xl, (myeloid cell leukaemia 1) Mcl-1, Bcl2-like protein 11 (BIM), (Bcl2-related ovarian killer protein) Bok, Bax and (Bcl2 homologous antagonist/killer) Bak in SiHa cells were detected using reverse transcription-quantitative PCR. ART inhibited the growth of SiHa cells in a dose-dependent manner. The IC of ART in SiHa cells was 26.32 µg/ml. According to the IC value, 15, 30 and 100 µg/ml ART were selected for further experiments, and normal saline (0 µg/ml ART) was used as the control group. The results indicated that treatment with 15, 30 and 100 µg/ml ART for 24 and 48 h induced apoptosis, increased the levels of ROS, the levels of Ca and the mRNA expression levels of BIM, Bok, Bax and Bak, but decreased the cell proliferation indices, the mitochondrial membrane potential and the mRNA expression levels of Bcl2, Bcl-xl and Mcl-1 in a dose- and time-dependent manner. In conclusion, ART inhibited the growth of SiHa cells and induced apoptosis via a mechanism associated with the regulation of Bcl2 family member expression, which was associated with the increase of the levels of ROS and Ca and the reduction of the mitochondrial membrane potential.

References

Estaquier J, Vallette F, Vayssiere J, Mignotte B . The mitochondrial pathways of apoptosis. Adv Exp Med Biol. 2012; 942:157-83. DOI: 10.1007/978-94-007-2869-1_7. View

Abanyie F, Acharya S, Leavy I, Bowe M, Tan K . Safety and Effectiveness of Intravenous Artesunate for Treatment of Severe Malaria in the United States-April 2019 Through December 2020. Clin Infect Dis. 2021; 73(11):1965-1972. PMC: 10959111. DOI: 10.1093/cid/ciab570. View

Diaz-Padilla I, Monk B, MacKay H, Oaknin A . Treatment of metastatic cervical cancer: future directions involving targeted agents. Crit Rev Oncol Hematol. 2012; 85(3):303-14. DOI: 10.1016/j.critrevonc.2012.07.006. View

Wang W, Zhu M, Xu Z, Li W, Dong X, Chen Y . Ropivacaine promotes apoptosis of hepatocellular carcinoma cells through damaging mitochondria and activating caspase-3 activity. Biol Res. 2019; 52(1):36. PMC: 6625015. DOI: 10.1186/s40659-019-0242-7. View

Wen L, Lv G, Zhao J, Lu S, Gong Y, Li Y . In vitro and in vivo Effects of Artesunate on Protoscoleces and Metacestodes. Drug Des Devel Ther. 2020; 14:4685-4694. PMC: 7646440. DOI: 10.2147/DDDT.S254166. View

Lefevre A, Leonard P . [Artesunate and severe malaria in paediatrics]. Rev Med Liege. 2019; 74(10):503-507. View

Chen S, Gan S, Han L, Li X, Xie X, Zou D . Artesunate induces apoptosis and inhibits the proliferation, stemness, and tumorigenesis of leukemia. Ann Transl Med. 2020; 8(12):767. PMC: 7333094. DOI: 10.21037/atm-20-4558. View

Li Q, Ni W, Deng Z, Liu M, She L, Xie Q . Targeting nasopharyngeal carcinoma by artesunate through inhibiting Akt/mTOR and inducing oxidative stress. Fundam Clin Pharmacol. 2017; 31(3):301-310. DOI: 10.1111/fcp.12266. View

Li Z, Dai H, Huang X, Feng J, Deng J, Wang Z . Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin. 2020; 42(2):301-310. PMC: 8026986. DOI: 10.1038/s41401-020-0478-3. View

10.

Warren C, Wong-Brown M, Bowden N . BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis. 2019; 10(3):177. PMC: 6384907. DOI: 10.1038/s41419-019-1407-6. View

11.

Kaloni D, Diepstraten S, Strasser A, Kelly G . BCL-2 protein family: attractive targets for cancer therapy. Apoptosis. 2022; 28(1-2):20-38. PMC: 9950219. DOI: 10.1007/s10495-022-01780-7. View

12.

Sharma S, Deep A, Sharma A . Current Treatment for Cervical Cancer: An Update. Anticancer Agents Med Chem. 2020; 20(15):1768-1779. DOI: 10.2174/1871520620666200224093301. View

13.

Saeed M, Cives-Losada C, Efferth T . Biomarker Expression Profiling in Cervix Carcinoma Biopsies Unravels WT1 as a Target of Artesunate. Cancer Genomics Proteomics. 2022; 19(6):727-739. PMC: 9620444. DOI: 10.21873/cgp.20355. View

14.

Holien T, Olsen O, Misund K, Hella H, Waage A, Ro T . Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate. Eur J Haematol. 2013; 91(4):339-46. DOI: 10.1111/ejh.12176. View

15.

Qian S, Wei Z, Yang W, Huang J, Yang Y, Wang J . The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Front Oncol. 2022; 12:985363. PMC: 9597512. DOI: 10.3389/fonc.2022.985363. View

16.

Abate M, Festa A, Falco M, Lombardi A, Luce A, Grimaldi A . Mitochondria as playmakers of apoptosis, autophagy and senescence. Semin Cell Dev Biol. 2019; 98:139-153. DOI: 10.1016/j.semcdb.2019.05.022. View

17.

Li T, Chen H, Liu X, Zhou Y, Bai S . [Immunoregulatory effect of artesunate on allergic contact dermatitis and its mechanism]. Yao Xue Xue Bao. 2012; 47(7):884-9. View

18.

Cao D, Chen D, Xia J, Wang W, Zhu G, Chen L . Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation. Biomed Pharmacother. 2022; 155:113705. DOI: 10.1016/j.biopha.2022.113705. View

19.

Tsuda K, Miyamoto L, Hamano S, Morimoto Y, Kangawa Y, Fukue C . Mechanisms of the pH- and Oxygen-Dependent Oxidation Activities of Artesunate. Biol Pharm Bull. 2018; 41(4):555-563. DOI: 10.1248/bpb.b17-00855. View

20.

Zhou X, Chen Y, Wang F, Wu H, Zhang Y, Liu J . Artesunate induces autophagy dependent apoptosis through upregulating ROS and activating AMPK-mTOR-ULK1 axis in human bladder cancer cells. Chem Biol Interact. 2020; 331:109273. DOI: 10.1016/j.cbi.2020.109273. View