Artesunate inhibits lung cancer cells via regulation of mitochondrial membrane potential and induction of apoptosis

Zhao,Yan; Liu,Jianghui; Liu,Liang

doi:10.3892/mmr.2020.11341

Artesunate inhibits lung cancer cells via regulation of mitochondrial membrane potential and induction of apoptosis

Authors:
- Yan Zhao
- Jianghui Liu
- Liang Liu
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Affiliations: Department of Otolaryngology and Head and Neck Surgery, Tumor Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China, Department of Flow Cytometry Analysis, Tumor Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
Published online on: July 15, 2020 https://doi.org/10.3892/mmr.2020.11341
Pages: 3017-3022

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Abstract

Lung cancer is a common malignant disease with a high incidence rate worldwide, posing a great threat to human health. To date, only a small number of studies have assessed the potential anti‑cancer effect of artesunate (Art) and the associated mechanisms in lung cancer. The present study aimed to investigate the inhibitory effects of Art in human lung cancer cells and investigated the underlying molecular mechanisms. The inhibitory effect of Art on the growth of A549 lung cancer cells was detected by the MTT assay, and flow cytometry was utilized to determine cell cycle progression, apoptosis, mitochondrial membrane potential, as well as the expression of Bcl‑2 and Bax proteins in A549 cells after Art treatment for 24 h. Art inhibited the growth of A549 cells in a dose‑dependent manner, induced cell apoptosis and cell cycle arrest, decreased the expression of Bcl‑2 protein and mitochondrial membrane potential, and increased the expression of Bax protein. In conclusion, Art significantly inhibited the growth of lung cancer cells by preventing cell cycle progression. This phenomenon indicated its promising therapeutic potential in the treatment of lung cancer.

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1	de Groot P and Munden RF: Lung cancer epidemiology, risk factors, and prevention. Radiol Clin North Am. 50:3017–876. 2012. View Article : Google Scholar
2	Kosacka M and Jankowska R: The epidemiology of lung cancer. Pneumonol Alergol Pol. 75:76–80. 2007.(In Polish). PubMed/NCBI
3	Radziszewska A, Karczmarek-Borowska B, Gradalska-Lampart M and Filip AA: Epidemiology, prevention and risk morbidity factors for lung cancer. Pol Merkur Lekarski. 38:113–118. 2015.(In Polish). PubMed/NCBI
4	Steliga MA and Dresler CM: Epidemiology of lung cancer: Smoking, secondhand smoke, and genetics. Surg Oncol Clin N Am. 20:605–618. 2011. View Article : Google Scholar : PubMed/NCBI
5	Tabchi S, Kassouf E, Rassy EE, Kourie HR, Martin J, Campeau MP, Tehfe M and Blais N: Management of stage III non-small cell lung cancer. Semin Oncol. 44:163–177. 2017. View Article : Google Scholar : PubMed/NCBI
6	Abuaku BK, Mensah BA, Ofori MF, Myers-Hansen J, Derkyi-Kwarteng AN, Essilfie F, Dokurugu M, Amoakoh E, Koram KA and Ghansah A: Efficacy of artesunate/amodiaquine in the treatment of uncomplicated malaria among children in Ghana. Am J Trop Med Hyg. 97:690–695. 2017. View Article : Google Scholar : PubMed/NCBI
7	Roussel C, Caumes E, Thellier M, Ndour PA, Buffet PA and Jaureguiberry S: Artesunate to treat severe malaria in travellers: review of efficacy and safety and practical implications. J Travel Med. doi:10.1093/jtm/taw093. PubMed/NCBI
8	Jauréguiberry S, Thellier M, Ndour PA, Ader F, Roussel C, Sonneville R, Mayaux J, Matheron S, Angoulvant A, Wyplosz B, et al French Artesunate Working Group, : Delayed-onset hemolytic anemia in patients with travel-associated severe malaria treated with artesunate, France, 2011–2013. Emerg Infect Dis. 21:804–812. 2015. View Article : Google Scholar : PubMed/NCBI
9	Raffray L, Receveur MC, Beguet M, Lauroua P, Pistone T and Malvy D: Severe delayed autoimmune haemolytic anaemia following artesunate administration in severe malaria: A case report. Malar J. 13:3982014. View Article : Google Scholar : PubMed/NCBI
10	Rolling T, Agbenyega T, Krishna S, Kremsner PG and Cramer JP: Delayed haemolysis after artesunate treatment of severe malaria - review of the literature and perspective. Travel Med Infect Dis. 13:143–149. 2015. View Article : Google Scholar : PubMed/NCBI
11	Greenshields AL, Fernando W and Hoskin DW: The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells. Exp Mol Pathol. 107:10–22. 2019. View Article : Google Scholar : PubMed/NCBI
12	Wang N, Chen H, Teng Y, Ding X, Wu H and Jin X: Artesunate inhibits proliferation and invasion of mouse hemangioendothelioma cells in vitro and of tumor growth in vivo. Oncol Lett. 14:6170–6176. 2017.PubMed/NCBI
13	Zheng L and Pan J: The anti-malarial drug artesunate blocks Wnt/β-catenin pathway and inhibits growth, migration and invasion of uveal melanoma cells. Curr Cancer Drug Targets. 18:988–998. 2018. View Article : Google Scholar : PubMed/NCBI
14	Verma S, Das P and Kumar VL: Chemoprevention by artesunate in a preclinical model of colorectal cancer involves down regulation of β-catenin, suppression of angiogenesis, cellular proliferation and induction of apoptosis. Chem Biol Interact. 278:84–91. 2017. View Article : Google Scholar : PubMed/NCBI
15	Vandewynckel YP, Laukens D, Geerts A, Vanhove C, Descamps B, Colle I, Devisscher L, Bogaerts E, Paridaens A, Verhelst X, et al: Therapeutic effects of artesunate in hepatocellular carcinoma: Repurposing an ancient antimalarial agent. Eur J Gastroenterol Hepatol. 26:861–870. 2014. View Article : Google Scholar : PubMed/NCBI
16	Jeong DE, Song HJ, Lim S, Lee SJ, Lim JE, Nam DH, Joo KM, Jeong BC, Jeon SS, Choi HY, et al: Repurposing the anti-malarial drug artesunate as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation of tumor growth, metastasis, and angiogenesis. Oncotarget. 6:33046–33064. 2015. View Article : Google Scholar : PubMed/NCBI
17	Kim C, Lee JH, Kim SH, Sethi G and Ahn KS: Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model. Oncotarget. 6:4020–4035. 2015. View Article : Google Scholar : PubMed/NCBI
18	Rasheed SA, Efferth T, Asangani IA and Allgayer H: First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases. Int J Cancer. 127:1475–1485. 2010. View Article : Google Scholar : PubMed/NCBI
19	Zhang L, Qian H, Sha M, Luan Z, Lin M, Yuan D, Li X, Huang J and Ye L: Downregulation of HOTAIR expression mediated anti-metastatic effect of artesunate on cervical cancer by inhibiting COX-2 expression. PLoS One. 11:e01648382016. View Article : Google Scholar : PubMed/NCBI
20	Alenzi FQ: Links between apoptosis, proliferation and the cell cycle. Br J Biomed Sci. 61:99–102. 2004. View Article : Google Scholar : PubMed/NCBI
21	Cvejic D, Selemetjev S, Savin S, Paunovic I and Tatic S: Changes in the balance between proliferation and apoptosis during the progression of malignancy in thyroid tumours. Eur J Histochem. 53:65–71. 2009. View Article : Google Scholar : PubMed/NCBI
22	Liu L, Zuo LF, Zuo J and Wang J: Artesunate induces apoptosis and inhibits growth of Eca109 and Ec9706 human esophageal cancer cell lines in vitro and in vivo. Mol Med Rep. 12:1465–1472. 2015. View Article : Google Scholar : PubMed/NCBI
23	Duma N, Santana-Davila R and Molina JR: Non-small cell lung cancer: Epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc. 94:1623–1640. 2019. View Article : Google Scholar : PubMed/NCBI
24	Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr, Wu YL and Paz-Ares L: Lung cancer: Current therapies and new targeted treatments. Lancet. 389:299–311. 2017. View Article : Google Scholar : PubMed/NCBI
25	von Hagens C, Walter-Sack I, Goeckenjan M, Osburg J, Storch-Hagenlocher B, Sertel S, Elsässer M, Remppis BA, Edler L, Munzinger J, et al: Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2). Breast Cancer Res Treat. 164:359–369. 2017. View Article : Google Scholar : PubMed/NCBI
26	Wang Z, Wang C, Wu Z, Xue J, Shen B, Zuo W, Wang Z and Wang SL: Artesunate suppresses the growth of prostatic cancer cells through inhibiting androgen receptor. Biol Pharm Bull. 40:479–485. 2017. View Article : Google Scholar : PubMed/NCBI
27	Li Q, Ni W, Deng Z, Liu M, She L and Xie Q: Targeting nasopharyngeal carcinoma by artesunate through inhibiting Akt/mTOR and inducing oxidative stress. Fundam Clin Pharmacol. 31:301–310. 2017. View Article : Google Scholar : PubMed/NCBI
28	Cui C, Feng H, Shi X, Wang Y, Feng Z, Liu J, Han Z, Fu J, Fu Z and Tong H: Artesunate down-regulates immunosuppression from colorectal cancer Colon26 and RKO cells in vitro by decreasing transforming growth factor β1 and interleukin-10. Int Immunopharmacol. 27:110–121. 2015. View Article : Google Scholar : PubMed/NCBI
29	Rassias DJ and Weathers PJ: Dried leaf Artemisia annua efficacy against non-small cell lung cancer. Phytomedicine. 52:247–253. 2019. View Article : Google Scholar : PubMed/NCBI
30	Yang Y, Wu N, Wu Y, Chen H, Qiu J, Qian X, Zeng J, Chiu K, Gao Q and Zhuang J: Artesunate induces mitochondria-mediated apoptosis of human retinoblastoma cells by upregulating Kruppel-like factor 6. Cell Death Dis. 10:8622019. View Article : Google Scholar : PubMed/NCBI
31	Wang N, Zeng GZ, Yin JL and Bian ZX: Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in Burkitts lymphoma. Biochem Biophys Res Commun. 519:533–539. 2019. View Article : Google Scholar : PubMed/NCBI
32	Li Y, Mu W, Ren J, Wuermanbieke S, Wahafu T, Ji B, Ma H, Amat A, Zhang K and Cao L: Artesunate alleviates interleukin-1β-induced inflammatory response and apoptosis by inhibiting the NF-κB signaling pathway in chondrocyte-like ATDC5 cells, and delays the progression of osteoarthritis in a mouse model. Int J Mol Med. 44:1541–1551. 2019.PubMed/NCBI
33	Chen X, Zhang XL, Zhang GH and Gao YF: Artesunate promotes Th1 differentiation from CD4+ T cells to enhance cell apoptosis in ovarian cancer via miR-142. Braz J Med Biol Res. 52:e79922019. View Article : Google Scholar : PubMed/NCBI
34	Chen P, Gu WL, Gong MZ, Wang J and Li DQ: Artesunate decreases beta-catenin expression, cell proliferation and apoptosis resistance in the MG-63 human osteosarcoma cell line. Cell Physiol Biochem. 43:1939–1949. 2017. View Article : Google Scholar : PubMed/NCBI
35	Nunes JJ, Pandey SK, Yadav A, Goel S and Ateeq B: Targeting NF-kappa B signaling by artesunate restores sensitivity of castrate-resistant prostate cancer cells to antiandrogens. Neoplasia. 19:333–345. 2017. View Article : Google Scholar : PubMed/NCBI
36	Jing W, Shuo L, Yingru X, Min M, Runpeng Z, Jun X and Dong H: Artesunate promotes sensitivity to sorafenib in hepatocellular carcinoma. Biochem Biophys Res Commun. 519:41–45. 2019. View Article : Google Scholar : PubMed/NCBI
37	Liu L, Zuo LF and Guo JW: Reversal of multidrug resistance by the anti-malaria drug artesunate in the esophageal cancer Eca109/ABCG2 cell line. Oncol Lett. 6:1475–1481. 2013. View Article : Google Scholar : PubMed/NCBI
38	Wang L, Liu L, Wang J and Chen Y: Inhibitory effect of artesunate on growth and apoptosis of gastric cancer cells. Arch Med Res. 48:623–630. 2017. View Article : Google Scholar : PubMed/NCBI
39	Wang L, Liu L, Chen Y, Du Y, Wang J and Liu J: Correlation between adenosine triphosphate (ATP)-binding cassette transporter G2 (ABCG2) and drug resistance of esophageal cancer and reversal of drug resistance by artesunate. Pathol Res Pract. 214:1467–1473. 2018. View Article : Google Scholar : PubMed/NCBI
40	Zhang P, Luo HS, Li M and Tan SY: Artesunate inhibits the growth and induces apoptosis of human gastric cancer cells by downregulating COX-2. OncoTargets Ther. 8:845–854. 2015. View Article : Google Scholar