Caution In Using Celecoxib: Induction Of VEGF And Angiogenesis By This COX-2 Inhibitor
H. Shu, H. Gao, K. Xu, Dept. of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, GAPurpose/Objective(s): Cyclooxygenase-2 (COX-2) plays a critical role in the initiation and maintenance of many cancer types and its elevated expression generally portends a worse prognosis. Given that increased COX-2 expression have been linked to increased angiogenesis, we became interested in assessing the response of glioma and other tumor cell lines to treatment with celecoxib (CXB), a selective COX-2 inhibitor. Materials/Methods: A number of glioma and other tumor cell lines were treated with varying concentrations of CXB. Vascular endothelial growth factor (VEGF) levels were determined at the mRNA level using RNase protection assays and at the protein level using ELISA. Sp1 and p38-MAPK silencing was accomplished pharmacologically with mithramycin and SB203580, respectively, or using specific siRNAs. Finally, VEGF mRNA levels were measured in xenograft flank tumors and in vivo angiogenesis was measured using a matrigel plug assay in nude mice after sustained oral administration of CXB. Results: Interestingly, contrary to its reported anti-angiogenic effects, we found that treatment with celecoxib (15-30 μM) actually induced the expression of VEGF mRNA and protein in multiple glioma cell lines. The degree of induction was comparable to, if not greater than, that found after exposure of these cells to hypoxia. This phenomenon was not restricted to glioma cell lines with multiple breast, colon, head and neck, and prostate carcinoma lines also showing similar responses at the mRNA level. Through experiments utilizing pharmacological inhibition and siRNA silencing of expression, p38-MAPK and the Sp1 transcription factor were both found to be required for CXB-induced VEGF expression. Consistent with the documented role of the Sp1 transcription factor in this effect, increased VEGF expression was found to be due to transcriptional activation and not changes in the stability of VEGF mRNA. Most importantly, this induction of VEGF was not only seen in vitro but could actually be detected with in vivo assays. Xenograft tumors from nude mice that have been fed CXB showed elevated mRNA expression of VEGF in comparison to tumors from mice that received vehicle only. Finally, oral administration of CXB in nude mice also resulted in increased angiogenesis as evidenced by higher hemoglobin content within CXB-treated plugs in the matrigel plug assay. Conclusions: CXB may, in some instances, enhance tumor cell expression of VEGF promoting angiogenesis and, consequently, may have detrimental effects on the response of tumors to this drug. Thus, we recommend caution in the use of CXB alone in the setting of cancer. However, these results do provide a strong rationale for exploring combination therapies where CXB is given with an anti-VEGF therapy.
Author Disclosure: H. Shu, None; H. Gao, None; K. Xu, None.
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