Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model.
We hypothesized that epidermal growth factor (EGF) receptor (EGFR) activation and vascular endothelial growth factor (VEGF)-induced angiogenic signals are important for the progression and metastasis of human salivary adenoid cystic carcinoma (ACC). To test this hypothesis, we evaluated the therapeutic effect of AEE788, a dual inhibitor of EGF and VEGF receptor (VEGFR) tyrosine kinases, on human salivary ACC. In clinical specimens of salivary ACC, EGF and VEGF signaling proteins were expressed at markedly higher levels than in adjacent normal glandular tissues. We examined the effects of AEE788 on salivary ACC cell growth and apoptosis and on the phosphorylation of EGFR and VEGFR-2 in salivary ACC cells. Treatment of salivary ACC cells with AEE788, alone or in combination with chemotherapy, led to growth inhibition, induction of apoptosis, and dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation. To determine the in vivo antitumor effects of AEE788, nude mice with orthotopic parotid tumors were randomized to receive oral AEE788 alone, paclitaxel alone, cisplatin alone, a combination of AEE788 plus paclitaxel, a combination of AEE788 plus cisplatin, or a placebo. AEE788 inhibited tumor growth and prevented lung metastasis in nude mice. To study the mechanism of interaction between AEE788 and chemotherapy, AEE788 was found to potentiate growth inhibition and apoptosis of ACC tumor cells mediated by chemotherapy. Tumors of mice treated with AEE788 and AEE788 plus chemotherapy exhibited down-regulation of activated EGFR and VEGFR-2, increased tumor and endothelial cell apoptosis, and decreased microvessel density, which correlated with a decrease in the level of matrix metalloproteinase-9 and matrix metalloproteinase-2 expression and a decrease in the incidence of vascular metastasis. These data show that EGFR and VEGFR can be molecular targets for therapy of salivary ACC.
Younes
Maher N
MN
Department of Head and Neck Surgery, Unit 441, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
Park
Young Wook
YW
Yazici
Yasemin Dakak
YD
Gu
Meirong
M
Santillan
Alfredo A
AA
Nong
Xiaolin
X
Kim
Seungwon
S
Jasser
Samar A
SA
El-Naggar
Adel K
AK
Myers
Jeffrey N
JN
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000627:therapeutic use; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017239:Paclitaxel; D010306:Parotid Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000627:therapeutic use* / Q000633:toxicity; D012468:Salivary Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D011687:Purines; D043823:Taxoids; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; D051058:Oncogene Protein v-akt; C489254:AEE 788; D017239:Paclitaxel; D002945:Cisplatin