Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing RET oncogenic rearrangement.
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a poor prognosis, therefore development of novel effective therapies is urgent. In the present study, we investigated the therapeutic efficacy of vandetanib (ZD6474), an inhibitor of VEGFR-2, EGFR and RET tyrosine kinases, in an orthotopic model of MPM. We found that a human MPM cell line, EHMES-10, expressed RET/PTC3 oncogenic rearrangement and a large amount of VEGF. Vandetanib induced the apoptosis and inhibited the proliferation of EHMES-10 cells in vitro (IC(50)=0.3 microM). Once-daily oral treatment with vandetanib inhibited tumor angiogenesis, and reduced significantly the growth of thoracic tumors and the production of pleural effusions, resulting in the prolonged survival of mice in EHMES-10 orthograft model. In contrast, the selective EGFR tyrosine kinase inhibitor, gefitinib, had no effect against EHMES-10 cells both in vitro and in vivo. Our results suggest that using vandetanib to target RET-dependent tumor cell proliferation and survival and VEGFR-2-dependent tumor angiogenesis may be promising against MPM expressing RET oncogenic rearrangement and VEGF.
Ogino
Hirokazu
H
Department of Internal Medicine and Molecular Therapeutics, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Yano
Seiji
S
Kakiuchi
Soji
S
Yamada
Tadaaki
T
Ikuta
Kenji
K
Nakataki
Emiko
E
Goto
Hisatsugu
H
Hanibuchi
Masaki
M
Nishioka
Yasuhiko
Y
Ryan
Anderson
A
Sone
Saburo
S
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077156:Gefitinib; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D010997:Pleural Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000096:biosynthesis* / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D010880:Piperidines; D011799:Quinazolines; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077156:Gefitinib; C452423:vandetanib