, Volume 10, Issue 4, pp 279–286 | Cite as

Anti-angiogenic effects of imatinib target smooth muscle cells but not endothelial cells

Original Paper


Knowing that progesterone up-regulates PDGF-A, which plays a relevant role in angiogenesis, and that imatinib mesylate targets PDGF receptor tyrosine kinase activity, the aim of the present study was to examine the effects of imatinib on Human Aortic Smooth Muscle Cells (HAoSMC) and Human Umbilical Vein Endothelial Cells (HUVEC) after incubation with progesterone. Expression of phosphorylated (activated) PDGFR-α was detected in HAoSMC, but in a very low extent in HUVEC. In agreement with the lack of active PDGFR-α, imatinib was unable to prevent HUVEC growth, survival or migration ability. In contrast, HAoSMC viability and proliferation were effectively inhibited by imatinib, as evaluated by MTT and BrdU incorporation assay, respectively. Corroborating these findings, a significant increase in the percentage of apoptotic cells was also observed after treatment with imatinib. Cell migration assays also showed a reduction in the migratory ability after incubation with imatinib. Altogether, these facts reveal that imatinib is able to affect HAoSMC survival, growth and migration. Furthermore, incubation with recombinant PDGF as well as, with progesterone seems to sustain PDGFR-α activity, prompting these cells to the inhibitory action of imatinib. These findings were restricted to smooth muscle cells, leading to the assumption that imatinib is probably preventing vessel stabilization, a crucial event for neovascular maturation. Our findings indicate that imatinib might be a good therapeutic agent against atherosclerosis and other vascular-associated disorders that carry in common smooth muscle cells abnormal growth.


Angiogenesis Apoptosis Cell growth Imatinib Migration PDGF Progesterone Tyrosine kinase 



We would like to thank Novartis Pharma (Basel, Switzerland) for providing imatinib. The authors are grateful to Novartis Oncology (Portugal) and FCT (POCI, FEDER, Programa Comunitário de Apoio) for the financial support that enabled this study.


  1. 1.
    Alvarez RH, Kantarjian HM, Cortes JE (2006) Biology of platelet-derived growth factor and its involvement in disease. Mayo Clin Proc 81(9):1241–1257PubMedCrossRefGoogle Scholar
  2. 2.
    Armulik A, Abramsson A, Betsholtz C (2005) Endothelial/Pericyte interactions. Circ Res 97:512–523PubMedCrossRefGoogle Scholar
  3. 3.
    Ault P (2007) Overview of second-generation tyrosine kinase inhibitors for patients with imatinib-resistant chronic myelogenous leukemia. Clin J Oncol Nurs 11:125–129PubMedCrossRefGoogle Scholar
  4. 4.
    Buchdunger E, O’Reilly T, Wood J (2002) Pharmacology of Imatinib (STI571). Eur J Cancer 38(5):S28–S36PubMedCrossRefGoogle Scholar
  5. 5.
    Carvalho I, Milanezi F, Martins A, Reis RM, Schmitt F (2005) Overexpression of platelet-derived growth factor receptor alpha in breast cancer is associated with tumour progression. Breast Cancer Res 7(5):R788–R795PubMedCrossRefGoogle Scholar
  6. 6.
    Chan P (2002) Developments in restenosis. J Renin Angiotensin Aldosterone Syst 3:145–149PubMedCrossRefGoogle Scholar
  7. 7.
    Chelouche D, Kim SJ, Onn A, Stone V, Nam DH, Yazici S, Fidler IJ, Price JE (2005) Inhibition of platelet-derived growth factor receptor signaling restricts the growth of human breast cancer in the bone of nude mice. Clin Cancer Res 11:306–314Google Scholar
  8. 8.
    Distler JW, Hirth A, Kurowska-Stolarska M, Gay RE, Gay S, Distler O (2003) Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 47:149–161PubMedGoogle Scholar
  9. 9.
    Edelberg JM, Lee SH, Kaur M, Tang L, Feirt NM, McCabe S, Bramwell O, Wong SC, Hong MK (2002) Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heart. Circulation 105(5):608–613PubMedCrossRefGoogle Scholar
  10. 10.
    Faivre EJ, Lange CA (2007) Progesterone receptors up-regulate Wnt-1 to induce EGFR transactivation and c-Src dependent sustained activation of Erk1/2 MAP kinase in breast cancer cells. Mol Cell Biol 27(2):466–480PubMedCrossRefGoogle Scholar
  11. 11.
    Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273–286PubMedCrossRefGoogle Scholar
  12. 12.
    George D (2001) Platelet-derived growth factor receptors: a therapeutic target in solid tumors. Semin Oncol 28(5 Suppl 17):27–33PubMedCrossRefGoogle Scholar
  13. 13.
    Hyder SM (2006) Sex-steroid regulation of vascular endothelial growth factor in breast cancer. Endocr relat Cancer 13:667–687PubMedCrossRefGoogle Scholar
  14. 14.
    Hyder SM, Chiappetta C, Stancel GM (2001) Pharmacological and endogenous progestins induce vascular endothelial growth factor expression in human breast cancer cells. Int J Cancer 92(4):469–473PubMedCrossRefGoogle Scholar
  15. 15.
    Jones RL, Judson IR (2005) The development and application of imatinib. Expert Opin Drug Saf 4(2):183–191PubMedCrossRefGoogle Scholar
  16. 16.
    Kantarjian HM, Cortes J (2006) New strategies in chronic myeloid leukemia. Int J Hematol 83(4):289–293PubMedCrossRefGoogle Scholar
  17. 17.
    Kim R, Emi M, Arihiro K, Tanabe K, Uchida Y, Toge T (2005) Chemosensitization by STI571 targeting the platelet-derived growth factor/Platelet-derived growth factor receptor-signaling pathway in the tumour progression and angiogenesis of gastric carcinoma. Cancer 103(9):1800–1809PubMedCrossRefGoogle Scholar
  18. 18.
    Kim SJ, Uehara H, Yazici S, Busby JE, Nakamura T, He J, Maya M, Logothetis C, Mathew P, Wang X, Do KA, Fan D, Fidler I (2006) Targeting platelet-derived growth factor receptor on endothelial cells of multidrug-resistant prostate ccancer. J Natl Cancer Inst 98(11):783–793PubMedCrossRefGoogle Scholar
  19. 19.
    Kvasnicka HM, Thiele J, Staib P, Schmitt-Graeff A, Griesshammer M, Klose J, Engels K, Kriener S (2004) Reversal of bone marrow angiogenesis in chronic myeloid leukemia following imatinib mesylate (STI571) therapy. Blood 103(9):3549–3551PubMedCrossRefGoogle Scholar
  20. 20.
    Liang Y, Hyder SM (2005) Proliferation of endothelial and tumor epithelial cells by progestin-induced vascular endothelial growth factor from human breast cancer cells: paracrine and autocrine effects. Endocrinology 146(8):3632–3641PubMedCrossRefGoogle Scholar
  21. 21.
    Machens HG, Morgan JR, Berthiaume F, Stefanovich P, Siemers F, Krapohl B, Berger A, Mailander P (2002) Platelet-derived growth factor-AA-mediated functional angiogenesis in the rat epigastric island flap after genetic modification of fibroblasts is ischemia dependent. Surgery 131(4):393–400PubMedCrossRefGoogle Scholar
  22. 22.
    Mauro MJ, Druker BJ (2001) STI571: targeting BCR-ABL as therapy for CML. Oncologist 6(3):233–238PubMedCrossRefGoogle Scholar
  23. 23.
    Mirkin S, Navarro F, Archer DF (2003) Hormone therapy and endometrial angiogenesis. Climacteric 6(4):273–277PubMedCrossRefGoogle Scholar
  24. 24.
    Nakamura Y, Suzuki T, Inoue T, Tazawa C, Ono K, Moriya T, Saito H, Ishibashi T, Takahashi S, Yamada S, Sasano H (2005) Progesterone receptor subtypes in vascular smooth muscle cells of human aorta. Endocr J 52(2):245–252PubMedCrossRefGoogle Scholar
  25. 25.
    Ostman A (2004) PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev 15:275–286PubMedCrossRefGoogle Scholar
  26. 26.
    Panigrahi I, Naithani R (2006) Imatinib mesylate: a designer drug. J Assoc Physicians India 54:203–206PubMedGoogle Scholar
  27. 27.
    Qin C, Liu Z (2007) In atherogenesis, the apoptosis of endothelial cell itself could directly induce over-proliferation of smooth muscle cells. Med Hypotheses 68:275–277PubMedCrossRefGoogle Scholar
  28. 28.
    Radford IR (2002) Imatinib. Novartis. Curr Opin Investig Drugs 3(3):492–499PubMedGoogle Scholar
  29. 29.
    Rocha A, Azevedo I, Soares R (2007) Progesterone sensitizes breast cancer MCF7 cells to imatinib inhibitory effects. J Cell Biochem (in press) (ISSN: 1097-4644)Google Scholar
  30. 30.
    Soares R, Guerreiro S, Botelho M (2007) Elucidating progesterone effects in breast cancer: cross talk with PDGF signalling pathway in smooth muscle cells. J Cell Biochem 100:174–183PubMedCrossRefGoogle Scholar
  31. 31.
    Tallquist M, Kazlauskas A (2004) PDGF signaling in cells and mice. Cytokine Growth Factor Rev 15(4):205–213PubMedCrossRefGoogle Scholar
  32. 32.
    Taylor C (2000) Platelet-derived growth factor activates porcine thecal cell phosphatidylinositol-3-kinase-Akt/PKB and ras-extracellular signal-regulated kinase-1/2 kinase signaling pathways via the platelet-derived growth factor-beta receptor. Endocrinology 141:1545–1553PubMedCrossRefGoogle Scholar
  33. 33.
    Tsutsumi N, Yonemitsu Y, Shikada Y, Onimaru M, Tanii M, Okano S, Kaneko K, Hasegawa M, Hashizume M, Maehara Y, Sueishi K (2004) Essential role of PDGFRalpha-p70S6K signaling in mesenchymal cells during therapeutic and tumor angiogenesis in vivo: role of PDGFRalpha during angiogenesis. Circ Res 94(9):1186–1194PubMedCrossRefGoogle Scholar
  34. 34.
    Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD, Fletcher JA, Demetri GD (2001) STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 20(36):5054–5058PubMedCrossRefGoogle Scholar
  35. 35.
    Walter LM, Rogers PAW, Girling JE (2005) The role of progesterone in endometrial angiogenesis in pregnant and ovariectomised mice. Reproduction 129:765–777PubMedCrossRefGoogle Scholar
  36. 36.
    Wu J, Richer J, Horwitz KB, Hyder SM (2004) Progestin-dependent induction of vascular endothelial growth factor in human breast cancer cells: preferential regulation by progesterone receptor B. Cancer Res 64(6):2238–2244PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2007

Authors and Affiliations

  1. 1.Department of Biochemistry (U38-FCT), Faculty of MedicineUniversity of PortoPortoPortugal

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