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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2002 Dec;93(12):1378–1385. doi: 10.1111/j.1349-7006.2002.tb01247.x

Microarray‐based Analysis of Anti‐angiogenic Activity of Demethoxycurcumin on Human Umbilical Vein Endothelial Cells: Crucial Involvement of the Down‐regulation of Matrix Metalloproteinase

Jin Hee Kim 1,†, Joong Sup Shim 1,†, Seok‐Ki Lee 2, Kyu‐Won Kim 2, Sun Young Rha 3, Hyun Cheol Chung 3, Ho Jeong Kwon 1,✉
PMCID: PMC5926931  PMID: 12495478

Abstract

cDNA microarray‐based gene expression analysis has been successfully employed to explore the action mechanism and to validate the targets of several drugs. In the present study, we evaluated anti‐angiogenic activity of demethoxycurcumin (DC), a structural analog of curcumin, isolated from Curcuma aromatica, and investigated the effect of DC on genetic reprogramming in cultured human umbilical vein endothelial cells (HUVECs) using cDNA microarray analysis. Of 1024 human cancer‐focused genes arrayed, 187 genes were up‐regulated and 72 genes were down‐regulated at least 2‐fold by DC. Interestingly, 9 angiogenesis‐related genes were down‐regulated over 5‐fold in response to DC, suggesting that the genetic reprogramming was crucially involved in anti‐angiogenesis by the compound. To verify the results obtained from cDNA microarray analysis, matrix metalloproteinase‐9 (MMP‐9), the product of one of the angiogenesis‐related genes down‐regulated over 5‐fold by DC, was investigated using gelatin zymography. DC potently inhibited the expression of MMP‐9, yet showed no direct effect on its activity. These data show that gene expressional change of MMP‐9 is a major mediator for angiogenesis inhibition by DC. All genes identified and microarray data are available on the web at http://dasan.sejong.ac.kr/bioprobe/.

Keywords: Demethoxycurcumin, Anti‐angiogenesis, DNA microarray, Matrix metalloproteinase

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REFERENCES

  • 1. ) Folkman , J. and Shing , Y.Angiogenesis . J. Biol. Chem. , 267 , 10931 – 11934 ( 1992. ). [PubMed] [Google Scholar]
  • 2. ) Hanahan , D. and Folkman , J.Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis . Cell , 86 , 353 – 364 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Kohn , E. C. , Alessandro , R. , Spoonster , J. , Wersto , R. P. and Liotta , L. A.Angiogenesis: role of calcium‐mediated signal transduction . Proc. Natl. Acad. Sci. USA , 92 , 1307 – 1311 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. ) Moscatelli , D. and Rifkin , D. B.Membrane matrix localization of proteases: a common theme in tumor invasion and angiogenesis . Biochim. Biophys. Acta , 945 , 67 – 85 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Weidner , N.Tumor angiogenesis and metastasis: correlation in invasive breast carcinoma . N. Engl. J. Med. , 324 , 1 – 8 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Kwon , H. J. , Kim , J. H. , Jung , H. J. , Kwon , Y. G. , Kim , M. Y. , Rho , J. R. and Shin , J. H.Anti‐angiogenic activity of acalycixenolide E, a novel marine natural product from Acalycigorgia inermis . J. Microbiol. Biotechnol. , 11 , 656 – 662 ( 2001. ). [Google Scholar]
  • 7. ) Kwon , H. J. , Kim , M. S. , Kim , M. J. , Nakajima , H. and Kim , K. W.Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis . Int. J. Cancer , 97 , 290 – 296 ( 2002. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Kelloff , G. J. , Crowell , J. A. , Hawk , E. T. , Steele , V. E. , Lubet , R. A. , Boone , C. W. , Covey , J. M. , Doody , L. A. , Ovenn , G. S. , Greenwald , P. , Hong , W. K. , Parkinson , D. R. , Bagheri , D. , Baxter , G. T. , Blunden , M. , Doletz , M. K. , Eisenhauer , K. M. , Johnson , K. , Knapp , G. G. , Longfellow , D. G. , Malone , W. R , Nayfield , S. G. , Seifried , H. E. , Swall , L. M. and Sigman , C. C.Strategy and planning for chemopreventive drug development: clinical development plans H . J. Cell. Biochem. , 26 , 54 – 71 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Arbiser , J. L. , Klauber , N. , Rohan , R. , van Leeuwen , R. , Huang , M. T. , Fisher , C. , Flynn , E. and Byers , H. R.Curcumin is an in vivo inhibitor of angiogenesis . Mol. Med. , 4 , 376 – 383 ( 1998. ). [PMC free article] [PubMed] [Google Scholar]
  • 10. ) Mosman , T.Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays . J. Immunol. Methods , 65 , 55 – 63 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Nissanov , J. , Tuman , R. W. , Graver , L. M. and Fortunato , J. M.Automatic vessel segmentation and quantification of the rat aortic ring assay of angiogenesis . Lab. Invest. , 73 , 734 – 739 ( 1995. ). [PubMed] [Google Scholar]
  • 12. ) Kruger , E. A. , Durgy , P. H. , Tsokos , M. G. , Venzon , D. J. , Libutti , S. K. , Dixon , S. C. , Rudek , M. A. , Plu , J. , Allegra , C. and Figg , W. D.Endostatin inhibits microvessel formation in the ex vivo rat aortic ring angiogenesis assay . Biochem. Biophys. Res. Commun. , 268 , 183 – 191 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Abedi , H. and Zachary , I.Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells . J. Biol. Chem. , 272 , 15442 – 15451 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Meadows , K. N. , Bryant , P. and Pumiglia , K.Vascular endothelial growth factor induction of the angiogenic phenotype requires ras activation . J. Biol. Chem. , 276 , 49289 – 49298 ( 2001. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Mandriota , S. J. , Menoud , P. A. and Pepper , M. S.Transforming growth factor β1 down‐regulates vascular endothelial growth factor receptor 2/flk‐1 expression in vascular endothelial cells . J. Biol. Chem. , 271 , 11500 – 11505 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Rao , C. V. , Rivenson , A. , Simi , B. and Reddy , B. S.Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound . Cancer Res. , 55 , 259 – 266 ( 1995. ). [PubMed] [Google Scholar]
  • 17. ) Huang , M. T. , Ma , W. , Lu , Y. P. , Chang , R. L. , Fisher , C. , Manchand , P. S. , Newmark , H. L. and Conney , A. H.Effects of curcumin, demethoxycurcumin, bisdemethoxy‐curcumin, and tetrahydrocurcumin on 12‐O‐tetrade‐canoylphorbol‐13‐acetate‐induced tumor promotion . Carcinogenesis , 16 , 2493 – 2497 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Khar , A. , Ali , A. M. , Pardhasaradhi , B. V. V. , Begum , Z. and Anjum , R.Antitumor activity of curcumin is mediated through the induction of apoptosis in AK‐5 tumor cells . FEES Lett. , 445 , 165 – 168 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Shim , J. S. , Lee , H. J. , Park , S. S. , Cha , B. G. and Chang , H. R.Curcumin‐induced apoptosis of A‐431 cells involves caspase‐3 activation . J. Biochem. Mol. Biol. , 34 , 189 – 193 ( 2001. ). [Google Scholar]
  • 20. ) Dinkova‐Kostova , A. T. and Talalay , P.Relation of structure of curcumin analogs to their potencies as inducers of phase 2 detoxification enzymes . Carcinogenesis , 20 , 911 – 914 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Masuda , T. , Hidaka , K. , Shinohara , A. , Maekawa , T. , Takeda , Y. and Yamaguchi , H.Chemical studies on antioxidant mechanism of curcuminoid: analysis of radical reaction products from curcumin . J. Agric. Food Chem. , 47 , 71 – 77 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Simon , A. , Allais , D. P. , Duroux , J. L. , Basly , J. P. , Durand‐Fontanier , S. and Delage , C.Inhibitory effect of curcuminoids on MCF‐7 cell proliferation and structure‐activity relationships . Cancer Lett. , 129 , 111 – 116 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Kiuchi , F , Goto , Y. , Sugimoto , N. , Akao , N. , Kondo , K. and Tsuda , Y.Nematocidal activity of turmeric: synergistic active of curcuminoids . Chem. Pharm. Bull. , 41 , 1640 – 1643 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Busiek , D. R , Ross , R P. , McDonnell , S. , Murphy , G. , Matrisian , L. M. and Welgus , H. G.The matrix metalloprotease matrilysin (PUMP) is expressed in developing human mononuclear phagocytes . J. Biol. Chem. , 267 , 9087 – 9092 ( 1992. ). [PubMed] [Google Scholar]
  • 25. ) Armstrong , D. G. and Jude , E. B.The role of matrix metal‐loproteinases in wound healing . J. Am. Podiatr. Med. Assoc. , 92 , 12 – 18 ( 2002. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Westermarck , J. and Kähäri , V.Regulation of matrix metalloproteinase expression in tumor invasion . FASEB J. , 13 , 781 – 792 ( 1999. ). [PubMed] [Google Scholar]
  • 27. ) Mohan , R. , Sivak , J. , Ashton , S. , Pham , L. A. , Kasahara , B. Q. , Raizman , M. B. and Fini , M. E.Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor‐2, including expression of matrix metalloproteinase, gelatinase B . J. Biol. Chem. , 275 , 10405 – 10412 ( 2000. ). [DOI] [PubMed] [Google Scholar]

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