Investigational New Drugs

, Volume 28, Issue 6, pp 800–811

Antimetastatic activity of MONCPT in preclinical melanoma mice model

  • Xiao-Chun Yang
  • Chong-Xing Tu
  • Pei-Hua Luo
  • Hong Zhu
  • Di-Feng Zhu
  • Hong-Hai Wu
  • Xing-Lu Zhou
  • Wei Lu
  • Qiao-Jun He
  • Bo Yang
PRECLINICAL STUDIES

Summary

Previous study demonstrated that MONCPT, a topoisomerase I inhibitor, exhibited potent anti-proliferation and anti-angiogenesis activity in vitro and in vivo. In this study, we report the efficacy of MONCPT against the development of melanoma metastasis by an intravenous injection of green fluorescent protein-transfected mice melanoma carcinoma (B16F10-GFP) cells in C57BL/6 mice. MONCPT (2.0, 5.0 and 12.5 mg/kg/2 days) markedly decreased B16F10-GFP pulmonary metastases by 12.8%, 53.1% and 76.3%, respectively; whereas higher doses of MONCPT (31.0 mg/kg/2 days) significantly inhibited the tumor growth of B16F10 xenograft model. In the in vitro experiment, MONCPT suppressed the B16F10-GFP cell invasion and migration without affecting cell survival. Further studies demonstrated that MONCPT decreased the secretion of matrix metalloproteinase (MMP)-9 and VEGF, and reduced the protein expression of HIF-1α as well as the phosphorylation level of ERK in B16F10-GFP cells. These in vivo and in vitro results indicate that MONCPT possesses both the potent antimetastatic ability and the tumor growth-inhibition activity, and the dual function promises MONCPT as a potential therapeutic agent for tumor metastasis and tumor growth of melanoma carcinoma.

Keywords

MONCPT Metastasis Melanoma Antitumor 

Abbreviations

MONCPT

10-Methoxy-9-nitrocamptothecin

GFP

green fluorescent protein

MMP

matrix metalloproteinase

HIF

hypoxia induced factor

VEGF

vascular endothelial growth factor

MAPK

Mitogen-activated protein kinase

Supplementary material

10637_2009_9323_Fig6_ESM.gif (151 kb)
Supp. 1

Histologic sections stained with H&E show lung metastatic lesions. (A) H&E staining of lungs of mice injected with B16F10-GFP (Black arrows: metastatic lesions; ×100). (B) H&E staining of lungs of normal C57BL/6 mice (×100). (152 KB)

10637_2009_9323_Fig6_ESM.tif (2.9 mb)
High Resolution Image(TIFF 2986 kb)
10637_2009_9323_Fig7_ESM.gif (5 kb)
Supp. 2

Effect of MONCPT on B16F10-GFP cells viability. 5 × 103 cells were seeded in 96 multiware. After 8 h attachment, replace with serum free medium and various dose of MONCPT were added. After 24 h, cell viability was determined by SRB assay. (8.00 KB)

10637_2009_9323_Fig7_ESM.tif (1.4 mb)
High Resolution Image(TIFF 1414 kb)

References

  1. 1.
    Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572CrossRefPubMedGoogle Scholar
  2. 2.
    Brinckerhoff CE, Matrisian LM (2002) Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 3(3):207–214CrossRefPubMedGoogle Scholar
  3. 3.
    Zucker S, Vacirca J (2004) Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev 23:101–117CrossRefPubMedGoogle Scholar
  4. 4.
    Hofmann UB, Houben R, Brocker EB, Becker JC (2000) Matrix metalloproteinases in human melanoma. J Invest Dermatol 115(3):337–344CrossRefPubMedGoogle Scholar
  5. 5.
    Rao JS (2003) Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 3(7):489–501CrossRefPubMedGoogle Scholar
  6. 6.
    Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25(1):9–34CrossRefPubMedGoogle Scholar
  7. 7.
    Cuvier C, Jang A, Hill RP (1997) Exposure to hypoxia, glucose starvation and acidosis: effect on invasive capacity of murine tumor cells and correlation with cathepsin (L 1 B)secretion. Clin Exp Metastasis 15:19–25CrossRefPubMedGoogle Scholar
  8. 8.
    Young SD, Marshall RS, Hill RP (1988) Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci 85:9533–9537CrossRefPubMedGoogle Scholar
  9. 9.
    Rofstad EK, Danielsen T (1999) Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br J Cancer 80(11):1697–1707CrossRefPubMedGoogle Scholar
  10. 10.
    Semenza GL (2001) Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 7:345–350CrossRefPubMedGoogle Scholar
  11. 11.
    Weidemann A, Johnson RS (2008) Biology of HIF-1alpha. Cell Death Differ 15:621–627CrossRefPubMedGoogle Scholar
  12. 12.
    Semenza G (2002) Singal transduction to hypoxia-inducible factor 1. Biochem Pharmacol 64:993–998CrossRefPubMedGoogle Scholar
  13. 13.
    Dor Y, Porat R, Keshet E (2001) Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. Am J Physiol Cell Physiol 280:C1367–C1374PubMedGoogle Scholar
  14. 14.
    Risau W (1997) Mechanisms of angiogenesis. Nature (Lond) 386:671–674CrossRefGoogle Scholar
  15. 15.
    Carmeliet P, Dor Y et al (1998) Role of HIF-1 in hypoxia-mediated apoptosis, cell proliferation and tumor angiogenesis. Nature 394:485–490CrossRefPubMedGoogle Scholar
  16. 16.
    Canning MT, Postovit LM, Clarke SH et al (2001) Oxygen-mediated regulation of gelatinase and tissue inhibitor of metalloproteinases-1 expression by invasive cells. Exp Cell Res 267:88–94CrossRefPubMedGoogle Scholar
  17. 17.
    Sun B, Zhang D, Zhang S, Zhang W, Guo H, Zhao X (2007) Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett 249(2):188–197CrossRefPubMedGoogle Scholar
  18. 18.
    Luo P, He Q, He X, Hu Y, Lu W, Cheng Y, Yang B (2006) Potent antitumor activity of 10-methoxy-9-nitrocamptothecin. Mol Cancer Ther 5:962–968CrossRefPubMedGoogle Scholar
  19. 19.
    Yang X, Luo P, Yang B, He Q (2006) Antiangiogenesis response of endothelial cells to the antitumour drug 10-methoxy-9-nitrocamptothecin. Pharmacol Res 54(5):334–340CrossRefPubMedGoogle Scholar
  20. 20.
    Wong ET, Berkenblit A (2004) The role of topotecan in the treatment of brain metastases. Oncologist. 9(1):68–79CrossRefPubMedGoogle Scholar
  21. 21.
    Shimada S, Hayashi N et al (2002) Irinotecan plus low-dose cisplatin for α-fetoprotein-producing gastric carcinoma with multiple liver metastases: report of two cases. Surg Today 32:1075–1080CrossRefPubMedGoogle Scholar
  22. 22.
    Douillard JY, Cunningham D et al (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355(9209):1041–1047CrossRefPubMedGoogle Scholar
  23. 23.
    Wani MC, Nicholas AW, Wall ME (1986) Plant antitumor agents. 23. Synthesis and antileukemic activity of camptothecin analogues. J Med Chem 29:2858–2863CrossRefGoogle Scholar
  24. 24.
    Yang B, Reynolds CP (2005) Tirapazamine cytotoxicity for neuroblastoma is p53 dependent. Clin Cancer Res 11:2774–2780CrossRefPubMedGoogle Scholar
  25. 25.
    Skehan P, Storeng R, Scudiero D et al (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112CrossRefPubMedGoogle Scholar
  26. 26.
    Zhu H, Huang M et al (2007) R16, a novel amonafide analogue, induces apoptosis and G2-M arrest via poisoning topoisomerase II. Mol Cancer Ther 6(2):484–495CrossRefPubMedGoogle Scholar
  27. 27.
    Zhang J, Shen Y, Liu J, Wei D (2005) Antimetastatic effect of prodigiosin through inhibition of tumor invasion. Biochem Pharmacol 69(3):407–414CrossRefPubMedGoogle Scholar
  28. 28.
    Nakagawa K, Sasaki Y, Kato S, Kubodera N, Okano T (2005) 22-Oxa-1alpha, 25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer. Carcinogenesis 26(6):1044–1054CrossRefPubMedGoogle Scholar
  29. 29.
    Huang Q, Shen HM, Ong CN (2004) Inhibitory effect of emodin on tumor invasion through suppression of activator protein-1 and nuclear factor-kappaB. Biochem Pharmacol 68(2):361–371CrossRefPubMedGoogle Scholar
  30. 30.
    Ying M, Tu C, Ying H, Hu Y, He Q, Yang B (2008) MSFTZ, a flavanone derivative, induces human hepatoma cell apoptosis via a reactive oxygen species- and caspase-dependent mitochondrial pathway. J Pharmacol Exp Ther 325(3):758–765CrossRefPubMedGoogle Scholar
  31. 31.
    Yang M, Jiang P et al (1999) Genetically fluorescent melanoma bone and organ metastasis models. Clin Cancer Res 5(11):3549–3559PubMedGoogle Scholar
  32. 32.
    Vihinen P, Kahari VM (2002) Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int J Cancer 99(2):157–166CrossRefPubMedGoogle Scholar
  33. 33.
    Ho LL, Chen WJ, Lin-Shiau SY, Lin JK (2002) Penta-O-galloyl-beta-Dglucose inhibits the invasion of mouse melanoma by suppressing metalloproteinase-9 through down-regulation of activator protein-1. Eur J Pharmacol 453(2–3):149–158CrossRefPubMedGoogle Scholar
  34. 34.
    Ellerbroek SM, Halbleib JM, Benavidez M, Warmka JK, Wattenberg EV, Stack MS et al (2001) Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association. Cancer Res 61(5):1855–1861PubMedGoogle Scholar
  35. 35.
    Westermarck J, Kahari VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13(8):781–792PubMedGoogle Scholar
  36. 36.
    Bischof P, Meisser A, Campana A (2002) Control of MMP-9 expression at the maternal-fetal interface. J Reprod Immunol 55(1–2):3–10CrossRefPubMedGoogle Scholar
  37. 37.
    Jiang BH, Jiang G, Zheng JZ, Lu Z, Hunter T, Vogt PK (2001) Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor1. Cell Growth Differ 12:363–369PubMedGoogle Scholar
  38. 38.
    Hur E, Chang KY, Lee E, Lee SK, Park H (2001) Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1alpha. Mol Pharmacol 59:1216–1224PubMedGoogle Scholar
  39. 39.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70CrossRefPubMedGoogle Scholar
  40. 40.
    Tiwari A, Kumar N, Bajpai R, Lal P (2007) Bone metastasis from ovarian cancer. J Cancer Res Ther 3(1):34–36CrossRefPubMedGoogle Scholar
  41. 41.
    Papadimitriou CA, Fountzilas G et al (2008) Paclitaxel, topotecan, and carboplatin in metastatic endometrial cancinoma: a Hellenic Co-operative Oncology Group (HeCOG) study. Gynecol Oncol 111(1):27–34 Epub 2008 Jul 21CrossRefPubMedGoogle Scholar
  42. 42.
    Yang M et al (2000) Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. Proc Natl Acad Sci 97(3):1206–1211CrossRefPubMedGoogle Scholar
  43. 43.
    Hoffman R et al (2002) Green fluorescent protein imaging of tumour growth, metastasis, and angiogenesis in mice models. Lancet Oncol 3(9):546–556CrossRefPubMedGoogle Scholar
  44. 44.
    Paris S, Sesboüé R (2004) Metastasis models: the green fluorescent revolution? Carcinogenesis 25(12):2285–2292CrossRefPubMedGoogle Scholar
  45. 45.
    Bogenrieder T, Herlyn M (2003) Axis of evil: molecular mechanisms of cancer metastasis. Oncogene 22:6524–6536CrossRefPubMedGoogle Scholar
  46. 46.
    Nabeshima K, Inoue T, Shimao Y, Sameshima T (2002) Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol Int 52:255–264CrossRefPubMedGoogle Scholar
  47. 47.
    Abiru S, Nakao K, Ichikawa T, Migita K, Shigeno M, Sakamoto M et al (2002) Aspirin and NS-398 inhibit hepatocyte growth factorinduced invasiveness of human hepatoma cells. Hepatology 35:1117–1124CrossRefPubMedGoogle Scholar
  48. 48.
    Shao ZM, Wu J, Shen ZZ, Barsky SH (1998) Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res 58:4851–4857PubMedGoogle Scholar
  49. 49.
    Reddy KB, Nabha SM, Atanaskova N (2003) Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev 22(4):395–403CrossRefPubMedGoogle Scholar
  50. 50.
    Qiao M, Sheng S, Pardee AB (2008) Metastasis and AKT activation. Cell Cycle 7(19):2991–2996 Epub 2008 Oct 13PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Xiao-Chun Yang
    • 1
  • Chong-Xing Tu
    • 1
  • Pei-Hua Luo
    • 1
  • Hong Zhu
    • 1
  • Di-Feng Zhu
    • 1
  • Hong-Hai Wu
    • 1
  • Xing-Lu Zhou
    • 1
  • Wei Lu
    • 2
  • Qiao-Jun He
    • 1
  • Bo Yang
    • 1
  1. 1.Institute of Pharmacology and Toxicology, College of Pharmaceutical SciencesZhejiang UniversityHangzhouPeople’s Republic of China
  2. 2.Shanghai Key Laboratory of Chemical BiologyEast China University of Science and TechnologyShanghaiPeople’s Republic of China

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