Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation.
Patients suffering from bone metastases of follicular thyroid carcinoma (FTC) have a poor prognosis because of the lack of effective treatment strategies. The overexpression of epidermal growth factor receptor (EGFR) associated with increased vascularity has been implicated in the pathogenesis of FTC and subsequent bone metastases. We hypothesized that inhibiting the phosphorylation of the EGFR and vascular endothelial growth factor receptor (VEGFR) by AEE788, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure. We tested this hypothesis using the human WRO FTC cell line. In culture, AEE788 inhibited the EGF-mediated phosphorylation of EGFR, VEGFR2, mitogen-activated protein kinase, and Akt in culture. AEE788, alone and in combination with paclitaxel, inhibited cell growth and induced apoptosis. When WRO cells were injected into the tibia of nude mice, tumor and endothelial cells within the lesions expressed phosphorylated EGFR, VEGFR, Akt, and mitogen-activated protein kinase that were inhibited by the oral administration of AEE788. Therapy consisting of orally given AEE788 and i.p. injected paclitaxel induced a high level of apoptosis in tumor-associated endothelial cells and tumor cells with the inhibition of tumor growth in the bone and the preservation of bone structure. Collectively, these data show that blocking the phosphorylation of EGFR and VEGFR with AEE788 combined with paclitaxel can significantly inhibit experimental human FTC in the bone of nude mice.
Younes
Maher Nabil
MN
Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Yigitbasi
Orhan Gazi
OG
Park
Young Wook
YW
Kim
Sun-Jin
SJ
Jasser
Samar A
SA
Hawthorne
Valerie Stone
VS
Yazici
Yasemin Dakak
YD
Mandal
Mahitosh
M
Bekele
Benjamin Nebiyou
BN
Bucana
Corazon D
CD
Fidler
Isaiah J
IJ
Myers
Jeffrey N
JN
D018263:Adenocarcinoma, Follicular / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D011687:Purines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C489254:AEE 788; D017239:Paclitaxel