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Artesunate inhibits melanoma progression in vitro via suppressing STAT3 signaling pathway

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Abstract

Background

Melanoma is a life-threatening cancer characterized with a potentially metastatic tumor of melanocytic origin. Improved methods or novel therapies are urgently needed to eliminate the development of metastases. Artesunate is a semi-synthetic derivative of artemisinin used for trarment of malaria and cancer. The purpose of this study was to investigate the anti-cancer effect of artesunate and the role on STAT3 signaling in A375 human melanoma cell line.

Methods

Melanoma cells were treated with artesunate at concentrations of 0–5 μM for 24 and 48 h. The inhibition of cell viability, colony formation, migration, invasion, adhesion, percentage of apoptotic cells, and expressions of signal transducer and activator of transcription-3 (STAT3) and related proteins were examined.

Results

Artesunate inhibited cellular proliferation of cancer cells by induction of apoptosis at sub-toxic doses. Cells treated with artesunate showed an inhibition in adhesion to extracellular matrix substrate matrigel and type IV collagen. Artesunate treatment showed a decreased cellular migration, invasion, and colony formation in melanoma cells. Artesunate also inhibited STAT3 and Src activations and STAT3 related protein expressions; such as metalloproteinase 2 (MMP-2), MMP-9, Mcl-1, Bxl-xL, vascular endothelial growth factor (VEGF), and Twist. Moreover, overexpression of constitutively active STAT3 in A375 cells attenuated the anti-proliferative, apoptotic and anti-invasive effects of artesunate.

Conclusion

The results obtained from this study demonstrated that the anticancer activity of artesunate occurred via STAT3 pathway and its target proteins. Therefore, it can be suggested that artesunate may be an important candidate molecule in the treatment of melanoma.

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References

  1. Chopra A, Sharma R, Rao UNM. Pathology of melanoma. Surg Clin North Am. 2020;100:43–59.

    Article  PubMed  Google Scholar 

  2. Rastrelli M, Tropea S, Rossi CR, Alaibac M. Melanoma: epidemiology, risk factors, pathogenesis, diagnosis and classification. Vivo. 2014;28:1005–11.

    Google Scholar 

  3. Bertolotto C. Melanoma: from melanocyte to genetic alterations and clinical options. Scientifica (Cairo). 2013;2013:635203.

    Google Scholar 

  4. Shellenberger R, Nabhan M, Kakaraparthi S. Melanoma screening: a plan for improving early detection. Ann Med. 2016;48:142–8.

    Article  CAS  PubMed  Google Scholar 

  5. Momtaz S, Niaz K, Maqbool F, Abdollahi M, Rastrelli L, Nabavi SM. STAT3 targeting by polyphenols: novel therapeutic strategy for melanoma. BioFactors. 2017;43:347–70.

    Article  CAS  PubMed  Google Scholar 

  6. Logotheti S, Pützer BM. STAT3 and STAT5 targeting for simultaneous management of melanoma and autoimmune diseases. Cancers (Basel). 2019;11:E1448.

    Article  Google Scholar 

  7. Fathi N, Rashidi G, Khodadadi A, Shahi S, Sharifi S. STAT3 and apoptosis challenges in cancer. Int J Biol Macromol. 2018;117:993–1001.

    Article  CAS  PubMed  Google Scholar 

  8. Raffetin A, Bruneel F, Roussel C, Thellier M, Buffet P, Caumes E, et al. Use of artesunate in non-malarial indications. Med Mal Infect. 2018;48:238–49.

    Article  CAS  PubMed  Google Scholar 

  9. Wu GD, Zhou HJ, Wu XH. Apoptosis of human umbilical vein endothelial cells induced by artesunate. Vascul Pharmacol. 2004;41:205–12.

    Article  CAS  PubMed  Google Scholar 

  10. Efferth T, Briehl MM, Tome ME. Role of antioxidant genes for the activity of artesunate against tumor cells. Int J Oncol. 2003;23:1231–5.

    CAS  PubMed  Google Scholar 

  11. Hamacher-Brady A, Stein HA, Turschner S, Toegel I, Mora R, Jennewein N, et al. Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem. 2011;286:6587–601.

    Article  CAS  PubMed  Google Scholar 

  12. Xu Q, Li ZX, Peng HQ, Sun ZW, Cheng RL, Ye ZM, et al. Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo. J Zhejiang Univ Sci B. 2011;12:247–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jiang Z, Chai J, Chuang HH, Li S, Wang T, Cheng Y, et al. Artesunate induces G0/G1 cell cycle arrest and iron-mediated mitochondrial apoptosis in A431 human epidermoid carcinoma cells. Anticancer Drugs. 2012;23:606–13.

    Article  CAS  PubMed  Google Scholar 

  14. Zhao Y, Jiang W, Li B, Yao Q, Dong J, Cen Y, et al. Artesunate enhances radiosensitivity of human non-small cell lung cancer A549 cells via increasing NO production to induce cell cycle arrest at G2/M phase. Int Immunopharmacol. 2011;11:2039–46.

    Article  CAS  PubMed  Google Scholar 

  15. Holien T, Olsen OE, Misund K, Hella H, Waage A, Rø TB, et al. Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate. Eur J Haematol. 2013;91:339–46.

    CAS  PubMed  Google Scholar 

  16. Slezakova S, Ruda-Kucerova J. Anticancer activity of artemisinin and its derivatives. Anticancer Res. 2017;37:5995–6003.

    CAS  PubMed  Google Scholar 

  17. Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR. The anti-malarial artesunate is also active against cancer. Int J Oncol. 2001;18:767–73.

    CAS  PubMed  Google Scholar 

  18. Besser D, Bromberg JF, Darnell JE Jr, Hanafusa H. A single amino acid substitution in the v-Eyk intracellular domain results in activation of Stat3 and enhances cellular transformation. Mol Cell Biol. 1999;19:1401–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ho WE, Peh HY, Chan TK, Wong WS. Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther. 2014;142:126–39.

    Article  CAS  PubMed  Google Scholar 

  20. Ilamathi M, Santhosh S, Sivaramakrishnan V. Artesunate as an anti-cancer agent targets Stat-3 and favorably suppresses hepatocellular carcinoma. Curr Top Med Chem. 2016;16:2453–63.

    Article  CAS  PubMed  Google Scholar 

  21. Tan M, Rong Y, Su Q, Chen Y. Artesunate induces apoptosis via inhibition of STAT3 in THP-1 cells. Leuk Res. 2017;62:98–103.

    Article  CAS  PubMed  Google Scholar 

  22. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63.

    Article  CAS  PubMed  Google Scholar 

  23. Chen T, Wang Y, Yang Y, Yu K, Cao X, Su F, et al. Gramicidin inhibits human gastric cancer cell proliferation, cell cycle and induced apoptosis. Biol Res. 2019;52:57.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Pilane MC, Bagla VP, Mokgotho MP, Mbazima V, Matsebatlela TM, Ncube I, et al. Free radical scavenging activity: antiproliferative and proteomics analyses of the differential expression of apoptotic proteins in MCF-7 cells treated with acetone leaf extract of Diospyros lycioides (Ebenaceae). Evid Based Complement Alternat Med. 2015;2015:534808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Qin F, Tang H, Zhang Y, Zhang Z, Huang P, Zhu J. Bone marrow-derived mesenchymal stem cell-derived exosomal microRNA-208a promotes osteosarcoma cell proliferation, migration, and invasion. J Cell Physiol. 2020;235:4734–45.

    Article  CAS  PubMed  Google Scholar 

  26. Harimaya Y, Koizumi K, Andoh T, Nojima H, Kuraishi Y, Saiki T. Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26–L5 carcinoma cells. Cancer Lett. 2002;187:121–7.

    Article  CAS  PubMed  Google Scholar 

  27. Ramacher M, Umansky V, Efferth T. Effect of artesunate on immune cells in ret-transgenic mouse melanoma model. Anticancer Drugs. 2009;20:910–7.

    Article  CAS  PubMed  Google Scholar 

  28. Wei S, Liu L, Chen Z, Yin W, Liu Y, Ouyang Q, et al. Artesunate inhibits the mevalonate pathway and promotes glioma cell senescence. J Cell Mol Med. 2020;24:276–84.

    Article  CAS  PubMed  Google Scholar 

  29. Osaki T, Uto Y, Ishizuka M, Tanaka T, Yamanaka N, Kurahashi T, et al. Artesunate enhances the cytotoxicity of 5-aminolevulinic acid-based sonodynamic therapy against mouse mammary tumor cells in vitro. Molecules. 2017;22:E533.

    Article  PubMed  Google Scholar 

  30. Kumar B, Kalvala A, Chu S, Rosen S, Forman SJ, Marcucci G, et al. Antileukemic activity and cellular effects of the antimalarial agent artesunate in acute myeloid leukemia. Leuk Res. 2017;59:124–35.

    Article  CAS  PubMed  Google Scholar 

  31. Chen X, Wong YK, Lim TK, Lim WH, Lin Q, Wang J, et al. Artesunate activates the intrinsic apoptosis of HCT116 cells through the suppression of fatty acid synthesis and the NF-κB pathway. Molecules. 2017;22(8):E1272.

    Article  PubMed  Google Scholar 

  32. Jiang W, Huang Y, Wang JP, Yu XY, Zhang LY. The synergistic anticancer effect of artesunate combined with allicin in osteosarcoma cell line in vitro and in vivo. Asian Pac J Cancer Prev. 2013;14:4615–9.

    Article  PubMed  Google Scholar 

  33. Michaelis M, Kleinschmidt MC, Barth S, Rothweiler F, Geiler J, Breitling R, et al. Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines. Biochem Pharmacol. 2010;79:130–6.

    Article  CAS  PubMed  Google Scholar 

  34. Yang Y, Zheng H, Zhan Y, Fan S. An emerging tumor invasion mechanism about the collective cell migration. Am J Transl Res. 2019;11:5301–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Aprioku JS. Early effects of concurrent administration of artesunate-amodiaquine and nifedipine on sperm parameters and sex hormones in guinea pigs: an experimental study. Int J Reprod Biomed (Yazd). 2018;16:629–36.

    Article  CAS  Google Scholar 

  36. Ma JD, **g J, Wang JW, Yan T, Li QH, Mo YQ, et al. A novel function of artesunate on inhibiting migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Res Ther. 2019;21:153.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liu Y, Gao S, Zhu J, Zheng Y, Zhang H, Sun H. Dihydroartemisinin induces apoptosis and inhibits proliferation, migration, and invasion in epithelial ovarian cancer via inhibition of the hedgehog signaling pathway. Cancer Med. 2018;7:5704–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang T, Luo R, Li W, Yan H, **e S, **ao W, et al. Dihydroartemisinin suppresses bladder cancer cell invasion and migration by regulating KDM3A and p21. J Cancer. 2020;11:1115–24.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Xu G, Zou WQ, Du SJ, Wu MJ, **ang TX, Luo ZG. Mechanism of dihydroartemisinin-induced apoptosis in prostate cancer PC3 cells: an iTRAQ-based proteomic analysis. Life Sci. 2016;157:1–11.

    Article  CAS  PubMed  Google Scholar 

  40. Humphries JD, Chastney MR, Askari JA, Humphries MJ. Signal transduction via integrin adhesion complexes. Curr Opin Cell Biol. 2019;56:14–21.

    Article  CAS  PubMed  Google Scholar 

  41. Chen H, Tao J, Wang J, Yan L. Artesunate prevents knee intraarticular adhesion via PRKR-like ER kinase (PERK) signal pathway. J Orthop Surg Res. 2019;14:448.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Turkson J. STAT proteins as novel targets for cancer drug discovery. Expert Opin Ther Targets. 2004;8:409–22.

    Article  CAS  PubMed  Google Scholar 

  43. Banerjee K, Resat H. Constitutive activation of STAT3 in breast cancer cells: a review. Int J Cancer. 2016;138:2570–8.

    Article  CAS  PubMed  Google Scholar 

  44. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002;21:2000–8.

    Article  CAS  PubMed  Google Scholar 

  45. Hao L, Ha JR, Kuzel P, Garcia E, Persad S. Cadherin switch from E- to N-cadherin in melanoma progression is regulated by the PI3K/PTEN pathway through twist and snail. Br J Dermatol. 2012;166:1184–97.

    Article  CAS  PubMed  Google Scholar 

  46. Moro N, Mauch C, Zigrino P. Metalloproteinases in melanoma. Eur J Cell Biol. 2014;93:23–9.

    Article  CAS  PubMed  Google Scholar 

  47. Pittayapruek P, Meephansan J, Prapapan O, Komine M, Ohtsuki M. Role of matrix metalloproteinases in photoaging and photocarcinogenesis. Int J Mol Sci. 2016;17:E868.

    Article  PubMed  Google Scholar 

  48. Teng Y, Ross JL, Cowell JK. The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. JAKSTAT. 2014;3:e28086.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was financially supported in part by the Office of Scientific Research Projects of Van Yuzuncu Yıl University under Grant number (TAP-2018-6956). The authors sincerely thank the laboratory technicians and assistants in Jagiellonian University, Medical Collage, Department of Food Chemistry and Nutrition, and Mr. Alexander B. Hunt for English language editing of the manuscript.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Pharmacy, Van Yuzuncu Yil University, Zeve Campus, 65080, Van, Turkey

    Mehmet Berköz

  2. Department of Basic Sciences, Faculty of Fisheries, Mersin University, 33160, Mersin, Turkey

    Ferbal Özkan-Yılmaz

  3. Department of Aquaculture, Faculty of Fisheries, Mersin University, 33160, Mersin, Turkey

    Arzu Özlüer-Hunt

  4. Department of Food Chemistry and Nutrition, Medical College, Jagiellonian University, 9 Medyczna St., Kraków, 30-688, Poland

    Mirosław Krośniak

  5. Department of Pharmaceutical Technology, Faculty of Pharmacy, Van Yuzuncu Yil University, Van, 65080, Turkey

    Ömer Türkmen

  6. Department of Medical Education, Faculty of Medicine, Van Yuzuncu Yil University, Van, 65080, Turkey

    Duygu Korkmaz

  7. Department of Biostatistics, Faculty of Medicine, Van Yuzuncu Yil University, Van, 65080, Turkey

    Sıddık Keskin

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Berköz, M., Özkan-Yılmaz, F., Özlüer-Hunt, A. et al. Artesunate inhibits melanoma progression in vitro via suppressing STAT3 signaling pathway. Pharmacol. Rep 73, 650–663 (2021). https://doi.org/10.1007/s43440-021-00230-6

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