title: Inhibition of vascular endothelial growth factor (VEGF)-165 and semaphorin 3A-mediated cellular invasion and tumor growth by the VEGF signaling inhibitor ZD4190 in human colon cancer cells and xenografts.
abstract: We recently showed by DNA microarray analysis that vascular endothelial growth factor (VEGF) receptor (VEGFR) is expressed in HCT8/S11 human colon cancer cells, suggesting that several angiogenic factors may target colon cancer cells themselves. In this study, transcripts encoding the VEGF-165 and semaphorin 3A (Sema3A) receptors and coreceptors Flt-1, KDR/Flk-1, plexin A1, and neuropilins NP-1 and NP-2 were identified by reverse transcription-PCR in the human colon cancer cell lines HCT8/S11, HT29, HCT116, and PCmsrc. Collagen invasion induced by VEGF-165 and Sema3A in HCT8/S11 cells (EC(50), 0.4-1 nmol/L) required p42/44 mitogen-activated protein kinase and signaling through RhoA/Rho-kinase-dependent and -independent pathways, respectively. As expected, the VEGFR signaling inhibitor ZD4190 selectively abrogated the proinvasive activity of VEGF in collagen gels (IC(50), 10 nmol/L) and chick heart fragments. We identify a novel function for VEGF-165 and Sema3A as proinvasive factors for human colorectal cancer cells. Interestingly, oral administration of the single drug ZD4190 to athymic mice (50 mg/kg/d, once daily) inhibited by 70% the growth of HCT8/S11 tumor cell xenografts. Combinations between the src tyrosine kinase inhibitor M475271 and ZD4190 or cisplatin resulted in additive therapeutic activity against LNM35 human lung tumor xenografts. Our data have significant implications for new therapeutic approaches and individualized treatment targeting VEGFR and src signaling pathways in combination with established clinical drugs at primary tumors and distant metastases in colon and lung cancer patients.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U673, Université Pierre et Marie Curie-Paris 6, Molecular and Clinical Oncology of Solid Tumors, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France.
authors.forename: Quang-Dé
authors.initials: QD
authors.lastname: Nguyen
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rodrigues
authors.forename: Christelle M
authors.initials: CM
authors.lastname: Rodrigue
authors.forename: Christine
authors.initials: C
authors.lastname: Rivat
authors.forename: Clara
authors.initials: C
authors.lastname: Grijelmo
authors.forename: Erik
authors.initials: E
authors.lastname: Bruyneel
authors.forename: Shahin
authors.initials: S
authors.lastname: Emami
authors.forename: Samir
authors.initials: S
authors.lastname: Attoub
authors.forename: Christian
authors.initials: C
authors.lastname: Gespach
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010880:Piperidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000187:drug effects / Q000378:metabolism; D040121:Semaphorin-3A / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C503850:4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-((1-methyl-4-piperidinyl) methoxy); D004791:Enzyme Inhibitors; D010880:Piperidines; D011799:Quinazolines; D040121:Semaphorin-3A; D014230:Triazoles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C405268:ZD 4190; D040262:Receptors, Vascular Endothelial Growth Factor; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin