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

Volumn 6, Issue 32, 2015, Pages 33046-33064

  Jeong, Da Eun ^a   Song, Hye Jin ^b   Lim, Sharon ^b   Lee, Se Jeong ^b   Lim, Joung Eun ^b   Nam, Do Hyun ^a,b   Joo, Kyeung Min ^a,b   Jeong, Byong Chang ^b   Jeon, Seong Soo ^b   Choi, Han Yong ^b   Lee, Hye Won ^b  

^a Sungkyunkwan University   (South Korea)

^b Sungkyunkwan University School of Medicine   (South Korea)

Author keywords

Artesunate; Drug repurposing; Metastasis; Oncosis; Renal cell carcinoma

Indexed keywords

ARTESUNATE; CD71 ANTIGEN; SORAFENIB; ANTIMALARIAL AGENT; ANTINEOPLASTIC AGENT; ARTEMISININ DERIVATIVE; LEUKOCYTE ANTIGEN; REACTIVE OXYGEN METABOLITE; TRANSFERRIN RECEPTOR;

ADULT; AGED; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CANCER PROGNOSIS; CANCER STAGING; CELL DEATH; CELL INVASION; CLONOGENESIS; COHORT ANALYSIS; CONCENTRATION RESPONSE; CONTROLLED STUDY; CYTOTOXICITY; DISTANT METASTASIS; DRUG MECHANISM; DRUG REPOSITIONING; FEMALE; G2 PHASE CELL CYCLE CHECKPOINT; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; KIDNEY METASTASIS; MAJOR CLINICAL STUDY; MALE; METASTASIS INHIBITION; PROTEIN EXPRESSION; RENAL CELL CARCINOMA CELL LINE; TISSUE MICROARRAY; TUMOR XENOGRAFT; UPREGULATION; ANIMAL; BAGG ALBINO MOUSE; CARCINOMA, RENAL CELL; CELL PROLIFERATION; DRUG EFFECTS; DRUG SCREENING; KIDNEY NEOPLASMS; METABOLISM; METASTASIS; MOUSE; NEOVASCULARIZATION, PATHOLOGIC; NUDE MOUSE; PATHOLOGY; PROGNOSIS; TUMOR CELL LINE; TUMOR INVASION; UMBILICAL VEIN ENDOTHELIAL CELL; VASCULARIZATION;

ANIMALS; ANTIGENS, CD; ANTIMALARIALS; ANTINEOPLASTIC AGENTS; ARTEMISININS; CARCINOMA, RENAL CELL; CELL DEATH; CELL LINE, TUMOR; CELL PROLIFERATION; FEMALE; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; HUMANS; KIDNEY NEOPLASMS; MICE; MICE, INBRED BALB C; MICE, NUDE; NEOPLASM INVASIVENESS; NEOPLASM METASTASIS; NEOVASCULARIZATION, PATHOLOGIC; PROGNOSIS; REACTIVE OXYGEN SPECIES; RECEPTORS, TRANSFERRIN; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84946064733     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.5422     Document Type: Article

References (72)

1. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005; 353:2477-2490.
2. Flanigan RC, Campbell SC, Clark JI, Picken MM. Metastatic renal cell carcinoma. Curr Treat Options Oncol. 2003; 4:385-390.
3. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009; 27:3584-3590.
4. Newman DJ, Cragg GM, Snader KM. The influence of natural products upon drug discovery. Nat Prod Rep. 2000; 17:215-234.
5. Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets. 2006; 7:407-421.
6. Li PC, Lam E, Roos WP, Zdzienicka MZ, Kaina B, Efferth T. Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Res. 2008; 68:4347-4351.
7. Efferth T, Benakis A, Romero MR, Tomicic M, Rauh R, Steinbach D, Hafer R, Stamminger T, Oesch F, Kaina B, Marschall M. Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron. Free Radic Biol Med. 2004; 37:998-1009.
8. Wang Z, Hu W, Zhang JL, Wu XH, Zhou HJ. Dihydroartemisinin induces autophagy and inhibits the growth of iron-loaded human myeloid leukemia K562 cells via ROS toxicity. FEBS Open Bio. 2012; 2:103-112.
9. Ba Q, Zhou N, Duan J, Chen T, Hao M, Yang X, Li J, Yin J, Chu R, Wang H. Dihydroartemisinin exerts its anticancer activity through depleting cellular iron via transferrin receptor-1. PLoS One. 2012; 7:e42703.
10. Nakase I, Lai H, Singh NP, Sasaki T. Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation. Int J Pharm. 2008; 354:28-33.
11. Hou J, Wang D, Zhang R, Wang H. Experimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res. 2008; 14:5519-5530.
12. Michaelis M, Kleinschmidt MC, Barth S, Rothweiler F, Geiler J, Breitling R, Mayer B, Deubzer H, Witt O, Kreuter J, Doerr HW, Cinatl J, Cinatl J Jr. Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines. Biochem Pharmacol. 2010; 79:130-136.
13. Zhou HJ, Wang Z, Li A. Dihydroartemisinin induces apoptosis in human leukemia cells HL60 via downregulation of transferrin receptor expression. Anticancer Drugs. 2008; 19:247-255.
14. Anfosso L, Efferth T, Albini A, Pfeffer U. Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics J. 2006; 6:269-278.
15. Zhou HJ, Wang WQ, Wu GD, Lee J, Li A. Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. Vascul Pharmacol. 2007; 47:131-138.
16. Rasheed SA, Efferth T, Asangani IA, 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. 2010; 127:1475-1485.
17. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995; 146:3-15.
18. Trump BF, Berezesky IK, Chang SH, Phelps PC. The pathways of cell death: oncosis, apoptosis, and necrosis. Toxicol Pathol. 1997; 25:82-88.
19. Du JH, Zhang HD, Ma ZJ, Ji KM. Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo. Cancer Chemother Pharmacol. 2010; 65:895-902.
20. Zhou X, Sun WJ, Wang WM, Chen K, Zheng JH, Lu MD, Li PH, Zheng ZQ. Artesunate inhibits the growth of gastric cancer cells through the mechanism of promoting oncosis both in vitro and in vivo. Anticancer Drugs. 2013; 24:920-927.
21. Robert A, Dechy-Cabaret O, Cazelles J, Meunier B. From mechanistic studies on artemisinin derivatives to new modular antimalarial drugs. Acc Chem Res. 2002; 35:167-174.
22. Golenser J, Waknine JH, Krugliak M, Hunt NH, Grau GE. Current perspectives on the mechanism of action of artemisinins. Int J Parasitol. 2006; 36:1427-1441.
23. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004; 5:863-873.
24. Daniels TR, Delgado T, Rodriguez JA, Helguera G, Penichet ML. The transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer. Clin Immunol. 2006; 121:144-158.
25. Zhao F, Wang H, Kunda P, Chen X, Liu QL, Liu T. Artesunate exerts specific cytotoxicity in retinoblastoma cells via CD71. Oncol Rep. 2013; 30:1473-1482.
26. Nakase I, Gallis B, Takatani-Nakase T, Oh S, Lacoste E, Singh NP, Goodlett DR, Tanaka S, Futaki S, Lai H, Sasaki T. Transferrin receptor-dependent cytotoxicity of artemisinintransferrin conjugates on prostate cancer cells and induction of apoptosis. Cancer Lett. 2009; 274:290-298.
27. Das AK. Anticancer Effect of AntiMalarial Artemisinin Compounds. Ann Med Health Sci Res. 2015; 5:93-102.
28. Weiss L, Harlos JP, Torhorst J, Gunthard B, Hartveit F, Svendsen E, Huang WL, Grundmann E, Eder M, Zwicknagl M, et al. Metastatic patterns of renal carcinoma: an analysis of 687 necropsies. J Cancer Res Clin Oncol. 1988; 114:605-612.
29. Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer. 2009; 10:281-289.
30. Liu WM. Enhancing the cytotoxic activity of novel targeted therapies-is there a role for a combinatorial approach. Curr Clin Pharmacol. 2008; 3:108-117.
31. Van Cruchten S, Van Den Broeck W. Morphological and biochemical aspects of apoptosis, oncosis and necrosis. Anat Histol Embryol. 2002; 31:214-223.
32. Liu X, Van Vleet T, Schnellmann RG. The role of calpain in oncotic cell death. Annu Rev Pharmacol Toxicol. 2004; 44:349-370.
33. Goll DE, Thompson VF, Li H, Wei W, Cong J. The calpain system. Physiol Rev. 2003; 83:731-801.
34. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003; 3:401-410.
35. Cao Y. Tumor angiogenesis and therapy. Biomed Pharmacother. 2005; 59:S340-343.
36. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004; 56:549-580.
37. Gupta K, Kshirsagar S, Li W, Gui L, Ramakrishnan S, Gupta P, Law PY, Hebbel RP. VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res. 1999; 247:495-504.
38. Sekhon BS. Repositioning drugs and biologics: Retargeting old/existing drugs for potential new therapeutic applications. J Pharm Educ Res. 2013; 4.
39. Chen JJ, Cai N, Chen GZ, Jia CC, Qiu DB, Du C, Liu W, Yang Y, Long ZJ, Zhang Q. The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma. Oncotarget. 2015; doi: 10.18632/oncotarget.4307 [Epub ahead of print].
40. Lamb R, Ozsvari B, Lisanti CL, Tanowitz HB, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease. Oncotarget. 2015; 6:4569-4584.
41. Sadowski MC, Pouwer RH, Gunter JH, Lubik AA, Quinn RJ, Nelson CC. The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer. Oncotarget. 2014; 5:9362-9381.
42. Triscott J, Lee C, Hu K, Fotovati A, Berns R, Pambid M, Luk M, Kast RE, Kong E, Toyota E, Yip S, Toyota B, Dunn SE. Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide. Oncotarget. 2012; 3:1112-1123.
43. Crespo-Ortiz MP, Wei MQ. Antitumor activity of artemisinin and its derivatives: from a well-known antimalarial agent to a potential anticancer drug. J Biomed Biotechnol. 2012; 2012:247597.
44. Gong Y, Gallis BM, Goodlett DR, Yang Y, Lu H, Lacoste E, Lai H, Sasaki T. Effects of transferrin conjugates of artemisinin and artemisinin dimer on breast cancer cell lines. Anticancer Res. 2013; 33:123-132.
45. Pantopoulos K, Hentze MW. Rapid responses to oxidative stress mediated by iron regulatory protein. EMBO J. 1995; 14:2917-2924.
46. Ha YM, Park MK, Kim HJ, Seo HG, Lee JH, Chang KC. High concentrations of ascorbic acid induces apoptosis of human gastric cancer cell by p38-MAP kinase-dependent up-regulation of transferrin receptor. Cancer Lett. 2009; 277:48-54.
47. Firestone GL, Sundar SN. Anticancer activities of artemisinin and its bioactive derivatives. Expert Rev Mol Med. 2009; 11:e32.
48. Lu JJ, Meng LH, Cai YJ, Chen Q, Tong LJ, Lin LP, Ding J. Dihydroartemisinin induces apoptosis in HL-60 leukemia cells dependent of iron and p38 mitogen-activated protein kinase activation but independent of reactive oxygen species. Cancer Biol Ther. 2008; 7:1017-1023.
49. Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med. 1997; 185:1481-1486.
50. Eguchi Y, Srinivasan A, Tomaselli KJ, Shimizu S, Tsujimoto Y. ATP-dependent steps in apoptotic signal transduction. Cancer Res. 1999; 59:2174-2181.
51. Lieberthal W, Menza SA, Levine JS. Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells. Am J Physiol. 1998; 274:F315-327.
52. Muller GJ, Stadelmann C, Bastholm L, Elling F, Lassmann H, Johansen FF. Ischemia leads to apoptosis-and necrosislike neuron death in the ischemic rat hippocampus. Brain Pathol. 2004; 14:415-424.
53. Shan J, Zhao W, Gu W. Suppression of cancer cell growth by promoting cyclin D1 degradation. Mol Cell. 2009; 36:469-476.
54. Yamamoto H, Ngan CY, Monden M. Cancer cells survive with survivin. Cancer Sci. 2008; 99:1709-1714.
55. Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer. 2007; 121:1360-1365.
56. Cole MD, Cowling VH. Transcription-independent functions of MYC: regulation of translation and DNA replication. Nat Rev Mol Cell Biol. 2008; 9:810-815.
57. Porter LA, Donoghue DJ. Cyclin B1 and CDK1: nuclear localization and upstream regulators. Prog Cell Cycle Res. 2003; 5:335-347.
58. Jiao Y, Ge CM, Meng QH, Cao JP, Tong J, Fan SJ. Dihydroartemisinin is an inhibitor of ovarian cancer cell growth. Acta Pharmacol Sin. 2007; 28:1045-1056.
59. Steinbruck L, Pereira G, Efferth T. Effects of artesunate on cytokinesis and G(2)/M cell cycle progression of tumour cells and budding yeast. Cancer Genomics Proteomics. 2010; 7:337-346.
60. Minner S, Rump D, Tennstedt P, Simon R, Burandt E, Terracciano L, Moch H, Wilczak W, Bokemeyer C, Fisch M, Sauter G, Eichelberg C. Epidermal growth factor receptor protein expression and genomic alterations in renal cell carcinoma. Cancer. 2012; 118:1268-1275.
61. Konkimalla VB, McCubrey JA, Efferth T. The role of downstream signaling pathways of the epidermal growth factor receptor for Artesunate's activity in cancer cells. Curr Cancer Drug Targets. 2009; 9:72-80.
62. Eder JP, Vande Woude GF, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 2009; 15:2207-2214.
63. Oh RR, Park JY, Lee JH, Shin MS, Kim HS, Lee SK, Kim YS, Lee SH, Lee SN, Yang YM, Yoo NJ, Lee JY, Park WS. Expression of HGF/SF and Met protein is associated with genetic alterations of VHL gene in primary renal cell carcinomas. APMIS. 2002; 110:229-238.
64. Rankin EB, Fuh KC, Castellini L, Viswanathan K, Finger EC, Diep AN, LaGory EL, Kariolis MS, Chan A, Lindgren D, Axelson H, Miao YR, Krieg AJ, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014; 111:13373-13378.
65. Suwaki N, Vanhecke E, Atkins KM, Graf M, Swabey K, Huang P, Schraml P, Moch H, Cassidy AM, Brewer D, Al-Lazikani B, Workman P, De-Bono J, et al. A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma. Sci Transl Med. 2011; 3:85ra47.
66. Efferth T, Ramirez T, Gebhart E, Halatsch ME. Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774. Biochem Pharmacol. 2004; 67:1689-1700.
67. Sieber S, Gdynia G, Roth W, Bonavida B, Efferth T. Combination treatment of malignant B cells using the antiCD20 antibody rituximab and the anti-malarial artesunate. Int J Oncol. 2009; 35:149-158.
68. Adnane L, Trail PA, Taylor I, Wilhelm SM. Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006; 407:597-612.
69. Vandewynckel YP, Laukens D, Geerts A, Vanhove C, Descamps B, Colle I, Devisscher L, Bogaerts E, Paridaens A, Verhelst X, Van Steenkiste C, Libbrecht L, Lambrecht BN, et al. Therapeutic effects of artesunate in hepatocellular carcinoma: repurposing an ancient antimalarial agent. Eur J Gastroenterol Hepatol. 2014; 26:861-870.
70. Cancer Genome Atlas Research N. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013; 499:43-49.
71. Lee HW, Park YM, Lee SJ, Cho HJ, Kim DH, Lee JI, Kang MS, Seol HJ, Shim YM, Nam DH, Kim HH, Joo KM. Alpha-smooth muscle actin (ACTA2) is required for metastatic potential of human lung adenocarcinoma. Clin Cancer Res. 2013; 19:5879-5889.
72. Lee HW, Joo KM, Lim JE, Cho HJ, Cho HJ, Park MC, Seol HJ, Seo SI, Lee JI, Kim S, Jeong BC, Nam DH. Tpl2 kinase impacts tumor growth and metastasis of clear cell renal cell carcinoma. Mol Cancer Res. 2013; 11:1375-1386.