Artemisinin and its derivatives are well known antimalarial drugs, particularly useful after resistance to traditional antimalarial pharmaceuticals has started to occur in Plasmodium falciparum. In recent years, anticancer activity of artemisinin has been reported both in vitro and in vivo. Artemisinin has inhibitory effects on cancer cell growth and anti-angiogenetic activity. In the present investigation, we analyzed the inhibitory effects of artemisinin on migratory ability of melanoma cell lines (A375P and A375M, low and medium metastatic properties, respectively). We demonstrate that artemisinin induces cell growth arrest in A375M, and affects A375P cells viability with cytotoxic and growth inhibitory effects, while it was not effective in contrasting proliferation of other tumor cell lines (MCF7 and MKN). In addition, artemisinin affected the migratory ability of A375M cells by reducing metalloproteinase 2 (MMP-2) production and down-regulating αvβ3 integrin expression. These findings introduce a potential of artemisinin as a chemotherapeutic agent in melanoma treatment.
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Soengas MS, Lowe SW (2003) Apoptosis and melanoma chemoresistance. Oncogene 22:3138–3151 doi:10.1038/sj.onc.1206454
Albelda SM, Mette SA, Elder DE, Stewart R, Damjanovich L, Herlyn M, Buck CA (1990) Integrin distribution in malignant melanoma: association of the beta 3 subunit with tumor progression. Cancer Res 50:6757–6764
van Kempen LC, van Muijen GN, Ruiter DJ (2007) Melanoma progression in a changing environment. Eur J Cell Biol 86:65–67 doi:10.1016/j.ejcb.2006.12.001
Dhingra V, Vishweshwar Rao K, Lakshmi Narasu M (2000) Current status of artemisinin and its derivatives as antimalarial drugs. Life Sci 66:279–300 doi:10.1016/S0024-3205(99)00356-2
Meshnick SR (2002) Artemisinin: mechanism of action, resistance and toxicity. Int J Parasitol 32:1655–1660 doi:10.1016/S0020-7519(02)00194-7
Wartenberg M, Wolf S, Budde P, Grünheck F, Acker H, Hescheler J, Wartenberg G, Sauer H (2003) The antimalaria agent artemisinin exerts antiangiogenic effects in mouse embryonic stem cell-derived embryoid bodies. Lab Invest 83:1647–1655 doi:10.1097/01.LAB.0000098424.38003.FF
Singh NP, Lai HC (2004) Artemisinin induces apoptosis in human cancer cells. Anticancer Res 24:2277–2280
Lee J, Zhou HJ, Wu XH (2006) Dihydroartemisinin downregulates vascular endothelial growth factor expression and induces apoptosis in chronic myeloid leukemia K562 cells. Cancer Chemother Pharmacol 57:213–220 doi:10.1007/s00280-005-0002-y
Lai H, Singh NP (2006) Oral artemisinin prevents and delays the development of 7,12-dimethylbenz[a] anthracene (DMBA)-induced breast cancer in the rat. Cancer Lett 231:43–48 doi:10.1016/j.canlet.2005.01.019
Lai H, Singh NP (1995) Selective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrin. Cancer Lett 91:41–46 doi:10.1016/0304-3835(94)03716-V
Lai H, Sasaki T, Singh NP, Messay A (2005) Effects of artemisinin-tagged holotransferrin on cancer cells. Life Sci 76:1267–1279 doi:10.1016/j.lfs.2004.08.020
Nakase I, Lai H, Singh NP, Sasaki T (2007) Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation. Int J Pharm 354:28–33 doi:10.1016/j.ijpharm.2007.09.003
D’Alessandro S, Gelati M, Basilico N, Parati EA, Haynes RK, Taramelli D (2007) Differential effects on angiogenesis of two antimalarial compounds, dihydroartemisinin and artemisone: implication for embryotoxicity. Toxicology 2:66–74 doi:10.1016/j.tox.2007.08.084
Dell’Eva R, Pfeffer U, Vené R, Anfosso L, Forlani A, Albini A, Efferth T (2004) Inhibition of angiogenesis in vivo and growth of Kaposi’s sarcoma xenograft tumors by the anti-malarial artesunate. Biochem Pharmacol 68:2359–2366 doi:10.1016/j.bcp.2004.08.021
Moore JC, Lai H, Li JR, Ren RL, McDougall JA, Singh NP, Chou CK (1995) Oral administration of dihydroartemisinin and ferrous sulfate retarded implanted fibrosarcoma growth in the rat. Cancer Lett 98:83–87
Wang J, Guo Y, Zhang BC, Chen ZT, Gao JF (2007) Induction of apoptosis and inhibition of cell migration and tube-like formation by dihydroartemisinin in murine lymphatic endothelial cells. Pharmacology 80:207–218 doi:10.1159/000104418
Gehlsen KR, Davis GE, Sriramarao P (1992) Integrin expression in human melanoma cells with differing invasive and metastatic properties. Clin Exp Metastasis 10:111–120 doi:10.1007/BF00114587
Nabeshima K, Inoue T, Shimao Y, Sameshima T (2002) Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol Int 52:255–264 doi:10.1046/j.1440-1827.2002.01343.x
Deryugina EI, Bourdon MA, Jungwirth K, Smith JW, Strongin AY (2000) Functional activation of integrin alpha v beta 3 in tumor cells expressing membrane-type 1 matrix metalloproteinase. Int J Cancer 86:15–23 doi:10.1002/(SICI)1097-0215(20000401)86:1<15::AID-IJC3>3.0.CO;2-B
Rolli M, Fransvea E, Pilch J, Saven A, Felding-Habermann B (2003) Activated integrin αvβ3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells. Proc Natl Acad Sci U S A 100:9482–9487 doi:10.1073/pnas.1633689100
Giancotti FG, Tarone G (2003) Positional control of cell fate through joint integrin/receptor protein kinase signaling. Annu Rev Cell Dev Biol 19:173–206 doi:10.1146/annurev.cellbio.19.031103.133334
Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25 doi:10.1016/0092-8674(92)90115-S
Mizejewski GJ (1999) Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med 222:124–138 doi:10.1046/j.1525-1373.1999.d01-122.x
Montgomery AM, Reisfeld RA, Cheresh DA (1994) Integrin αvβ3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Natl Acad Sci U S A 91:8856–8860 doi:10.1073/pnas.91.19.8856
Chan BM, Matsuma N, Tabada Y, Zetter BR, Hemier M (1991) In vitro and in vivo consequences of the VLA-2 expression on rhabdomyosarcoma cells. Science 251:1600–1602 doi:10.1126/science.2011740
Brooks PC, Stromblad S, Klemke D, Sarkar FH, Cheresh DA (1995) Anti-integrin αv β3 blocks human breast cancer growth and angiogenesis. J Clin Invest 96:1815–1822 doi:10.1172/JCI118227
Koukoulis GK, Howeedy AA, Korhonen M, Virtanen I, Gould VE (1993) Distribution of tenascin, cellular fibronectins, and integrins in the normal, hyperplastic, and neoplastic breast. J Submicrosc Cytol Pathol 25:285–293
This study was supported by grants from Legge 5 (2006), Regione Campania.
The first two authors (E.B. and A.B.) equally contributed to this work.
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Buommino, E., Baroni, A., Canozo, N. et al. Artemisinin reduces human melanoma cell migration by down-regulating αVβ3 integrin and reducing metalloproteinase 2 production. Invest New Drugs 27, 412–418 (2009). https://doi.org/10.1007/s10637-008-9188-2