Cole George W, Alleva Annette M, Zuo Jing T, Sehgal Shailen S, Yeow Wen-Shuz, Schrump David S, Nguyen Dao M
Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Anticancer Res. 2006 Mar-Apr;26(2A):809-21.
This study aimed to evaluate the impact of selective abrogation of either the MEK/ERK1/2 (UO126 or PD98059) or the PI3K/AKT (LY294002) signaling cascade on cell proliferation, motility and invasion and production of VEGF (collectively termed pro-metastasis phenotypes) in cultured malignant pleural mesothelioma (MPM) cells.
Treatment-induced cytotoxicity was evaluated by MTT or Annexin V assays. Cell motility was assessed by wound healing and Matrigel invasion assays. VEGF in conditioned media of cancer cells was measured by ELISA.
LY294002 and UO126 significantly inhibited cell proliferation and clonogenicity of MPM cells in vitro. A substantial reduction of cell motility, Matrigel invasion as well as inhibition of basal or EGF-induced VEGF production were observed in drug-treated cells.
The selective MEK or PI3K kinase inhibitors are equally effective in down-regulating the expression of pro-metastasis phenotypes, suggesting that MEK or PI3K are appropriate targets for the development of molecular therapeutics for malignant pleural mesothelioma.
本研究旨在评估选择性阻断MEK/ERK1/2（UO126或PD98059）或PI3K/AKT（LY294002）信号级联反应对培养的恶性胸膜间皮瘤（MPM）细胞增殖、运动、侵袭以及血管内皮生长因子（VEGF）产生（统称为促转移表型）的影响。
通过MTT或膜联蛋白V检测评估治疗诱导的细胞毒性。通过伤口愈合和基质胶侵袭检测评估细胞运动。采用酶联免疫吸附测定法检测癌细胞条件培养基中的VEGF。
LY294002和UO126显著抑制MPM细胞在体外的增殖和克隆形成能力。在药物处理的细胞中观察到细胞运动、基质胶侵袭显著降低，以及基础或表皮生长因子诱导的VEGF产生受到抑制。
选择性MEK或PI3K激酶抑制剂在下调促转移表型的表达方面同样有效，这表明MEK或PI3K是开发恶性胸膜间皮瘤分子治疗药物的合适靶点。
