Targeting tumor angiogenesis in thoracic malignancies using MEK pharmacologic inhibitor: in vitro and in vivo analysis
Shailen Sehgal2, Wen-Shuz Yeow2, Mustafa Hussain2, Amy Loehfelm2, Joseph Blansfield2, Steven K. Libutti2, Craig Thomas2, Dao M. Nguyen1; 1Surgery, University of Miami, Miami, FL; 2National Cancer Institute, National Institutes of Health, Bethesda, MD
Comment on this Abstract
Objective: Constitutive active MEK/ERK1,2 signaling in tumor cells promotes their malignant potentials via up-regulation of proliferation, survival, motility/invasion, angiogenesis thus making this pathway an attractive target for cancer therapy. Unless harboring B-raf mutations (rare in thoracic cancers) tumors are resistant to the antiproliferative effect of MEK inhibitors (MEKIs). This study aims to evaluate the antiangiogenesis effect of MEKIs UO126 and PD148352 in thoracic cancer cells (TCC).
Methods: 5 lung, 6 mesothelioma, 6 esophageal cancer cell lines and primary human umbilical endothelial cells (HUVEC) were treated with UO126 and cell viability was determined by MTT assay. Levels of pro-angiogenesis cytokines VEGF, IL8, prostaglandin E2 in supernatant of cancer cells were measured by ELISA. Total and phosphorylated MEK or ERK were determined by western blots. The in vivo growth inhibitory effect of UO126 was studied in nude mice bearing subcutaneous H513 mesothelioma xenografts.
Results: UO126 mediated profoundly inhibition of MEK-mediated ERK1/2 phosphorylation and suppression of cell proliferation via cell cycle arrest at G0/S checkpoint with IC50's ranging from 10.0±2.0 to 42.0±4.5 μM in TCC. UO126 substantially suppressed the production of pro-angiogenesis cytokines VEGF, IL-8 and prostaglandin E2 (product of COX2 activity) at drug concentrations well below growth IC50's (range: 0.5 to 20 μM). Conditioned media of UO126-treated TCC with depleted pro-angiogenesis cytokines did not support viability of HUVECs. UO126 directly inhibited HUVEC growth and strongly abrogated the angiogenesis functions of endothelial cells (proliferation, migration, invasion of extracellular matrix and tube formation) as shown by the rat aortic ring assay. Similar in vitro findings were observed using the clinically relevant MEKI PD148352 (CI-1040). Daily administration of UO126 at either 20 mg/kg or 40 mg/kg to nude mice bearing H513 tumor xenografts resulted in statistically significant suppression of tumor growth (Figure 1).
Conclusion: MEKIs exert their antitumor effect directly by inhibiting tumor cell proliferation and indirectly by anti-angiogenesis mechanism via suppression of tumor-derived production of pro-angiogenesis cytokines and abrogation of endothelial cell functions. As angiogenesis is essential for metastasis development, ongoing efforts are focused on evaluating MEKIs as anti-metastasis drugs which may particularly be useful in chemopreventive or postoperative adjuvant settings.
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