Enhancement of anti-tumor activity by low-dose combination of the recombinant urokinase kringle domain and celecoxib in a glioma model.
The kringle domain of urokinase-type plasminogen activator (UK1) has anti-angiogenic and anti-tumor effects. Celecoxib, an inhibitor of cyclooxygenase type 2, also suppresses angiogenesis and tumor growth. To look for potential additive effects in their activities, we examined the anti-angiogenic and anti-tumor effects of the combination of UK1 and celecoxib for malignant gliomas. In vitro, the combination of UK1 and celecoxib enhanced inhibition of proliferation, migration, and tube formation of endothelial cells, although showing no enhancement of inhibition of U87 cell growth. However, in vivo models, combination treatment of intracerebral U87 malignant glioma xenografts in nude mice with UK1 (10mg/kg/day) and celecoxib (10mg/kg/day) at lower doses resulted in even more potent inhibition of tumor growth than each monotherapy (by 81% compared to untreated tumors), with drastic decrease of the expression of angiogenesis-related factors and increase of apoptosis in the tumor tissues. Interestingly, UK1 inhibited VEGF or bFGF-induced phosphorylation of ERK1/2 in ECs, whereas celecoxib showed no such effects. However, celecoxib inhibited U87 cell growth and directly suppressed their VEGF production. Therefore, our data suggest that combined use at low doses of UK1 and celecoxib with different anti-angiogenic mechanisms provides a desirable strategy for anti-glioma therapy.
Kim
Chung Kwon
CK
Cancer Research Institute, The Catholic University of Korea, Seoul, Republic of Korea.
Joe
Young Ae
YA
Lee
Suk-Keun
SK
Kim
Eun-Kyoung
EK
O
Eunju
E
Kim
Hyun-Kyung
HK
Oh
Bae Jun
BJ
Hong
Sung Hee
SH
Hong
Yong-Kil
YK
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018082:Kringles; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation; D011720:Pyrazoles / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D013997:Time Factors; D047368:Tumor Burden; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage* / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D011994:Recombinant Proteins; D013449:Sulfonamides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D014568:Urokinase-Type Plasminogen Activator; D000068579:Celecoxib