Antiangiogenic activities of 2,5-dimethyl-celecoxib on the tumor vasculature.
Our laboratory has previously shown that a novel compound, 2,5-dimethyl-celecoxib (DMC), which is structurally similar to the cyclooxygenase-2 (COX-2) inhibitor celecoxib but lacks the COX-2-inhibitory function, mimics the antitumor effects of celecoxib. Most studies on DMC, however, focused on its effects on tumor cells. Here, we investigated the activities of DMC as an antiangiogenic agent in both in vitro and in vivo systems. Using primary cultures of human glioma specimens, we found that DMC treatment was cytotoxic to tumor-associated brain endothelial cells (TuBEC), which was mediated through the endoplasmic reticulum stress pathway. In contrast, confluent cultures of quiescent human BEC did not undergo cell death. DMC potently suppressed the proliferation and migration of the TuBEC. DMC caused no apparent effects on the secretion of vascular endothelial growth factor and interleukin-8 but inhibited the secretion of endothelin-1 in tumor-associated EC. DMC treatment of glioma xenografts in mice resulted in smaller tumors with a pronounced reduction in microvessel density compared with untreated mice. In vitro and in vivo analyses confirmed that DMC has antivascular activity. Considering that DMC targets both tumor cells and tumor-associated ECs, this agent is a promising anticancer drug.
Virrey
Jenilyn J
JJ
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Liu
Zhi
Z
Cho
Hee-Yeon
HY
Kardosh
Adel
A
Golden
Encouse B
EB
Louie
Stan G
SG
Gaffney
Kevin J
KJ
Petasis
Nicos A
NA
Schönthal
Axel H
AH
Chen
Thomas C
TC
Hofman
Florence M
FM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C506698:2,5-dimethylcelecoxib; D020533:Angiogenesis Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides