title: The malignant progression effects of regorafenib in human colon cancer cells.
abstract: A number of anti-angiogenic drugs targeting vascular endothelial growth factor receptors (VEGF-R) have developed and enabled significant advances in cancer therapy including colorectal cancer. However, acquired resistance to the drugs occurs, leading to disease progression, such as invasion and metastasis. How tumors become the resistance and promote their malignancy remains fully uncertain. One of possible mechanisms for the resistance and the progression may be the direct effect of VEGF-R inhibitors on tumor cells expressing VEGF-R. We investigated here the direct effect of a VEGF-R-targeting agent, regorafenib, which is the first small molecule inhibitor of VEGF-Rs for the treatment of patients with colorectal cancer, on phenotype changes in colon cancer HCT116 cells. Treatment of cells with regorafenib for only 2 days activated cell migration and invasion, while vehicle-treated control cells showed less activity. Intriguingly, chronic exposure to regorafenib for 90 days dramatically increased migration and invasion activities and induced a resistance to hypoxia-induced apoptosis. These results suggest that loss of VEGF signaling in cancer cells may induce the acquired resistance to VEGF/VEGF-R targeting therapy by gaining two major malignant phenotypes, apoptosis resistance and activation of migration/invasion.
authors.affiliation: Department of Physiological Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School.
authors.forename: Chisato
authors.initials: C
authors.lastname: Tomida
authors.forename: Kana
authors.initials: K
authors.lastname: Aibara
authors.forename: Naoko
authors.initials: N
authors.lastname: Yamagishi
authors.forename: Chiaki
authors.initials: C
authors.lastname: Yano
authors.forename: Hikaru
authors.initials: H
authors.lastname: Nagano
authors.forename: Tomoki
authors.initials: T
authors.lastname: Abe
authors.forename: Ayako
authors.initials: A
authors.lastname: Ohno
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirasaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nikawa
authors.forename: Shigetada
authors.initials: S
authors.lastname: Teshima-Kondo
mesh_terms: D017209:Apoptosis; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D045325:HCT116 Cells; D006801:Humans; D009361:Neoplasm Invasiveness; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D040262:Receptors, Vascular Endothelial Growth Factor