Department of Integrated Medicine and Informatics, Ehime University Graduate School of Medicine, Ehime, Japan.
Int J Oncol. 2012 Aug;41(2):449-56. doi: 10.3892/ijo.2012.1462. Epub 2012 May 8.
Malignant pleural mesothelioma (MPM) is an aggressive malignancy for which there is no approved targeted therapy. We examined the therapeutic efficacy of the mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors against human MPM cell lines both in vitro and orthotopically inoculated into severe combined immunodeficient (SCID) mice. In addition, the molecular mechanisms of these agents were confirmed in vitro and in vivo. The MEK or the PI3K inhibitor suppressed MPM cell growth in vitro in a dose-dependent manner via induction of G1 cell cycle arrest and apoptosis. In addition, combined use of the MEK and PI3K inhibitors showed an additive or synergistic inhibitory effect on MPM cell growth compared to treatment with either individual drug. Treatment with MEK or PI3K inhibitor suppressed the production of thoracic tumors and pleural effusion and prolonged the survival time of EHMES-10 cell-bearing SCID mice. The combination therapy more effectively prolonged the survival time compared to treatment with either individual drug. Immunohistochemical and western blot analysis of thoracic tumors suggested that these agents induced cell cycle arrest, apoptosis and inhibition of tumor angiogenesis. Our results suggest that a combination of MEK and PI3K inhibitors is a promising therapeutic strategy for MPM.
恶性胸膜间皮瘤（MPM）是一种侵袭性恶性肿瘤，目前尚无批准的靶向治疗药物。我们研究了丝裂原活化蛋白激酶激酶（MEK）和磷脂酰肌醇 3-激酶（PI3K）抑制剂对人 MPM 细胞系的治疗效果，包括体外和原位接种到严重联合免疫缺陷（SCID）小鼠中。此外，还在体外和体内证实了这些药物的分子机制。MEK 或 PI3K 抑制剂通过诱导 G1 细胞周期阻滞和细胞凋亡，以剂量依赖的方式抑制 MPM 细胞在体外的生长。此外，与单独使用任何一种药物相比，联合使用 MEK 和 PI3K 抑制剂对 MPM 细胞生长具有相加或协同抑制作用。MEK 或 PI3K 抑制剂的治疗抑制了胸肿瘤和胸腔积液的产生，并延长了 EHMES-10 细胞荷瘤 SCID 小鼠的生存时间。与单独使用任何一种药物相比，联合治疗更有效地延长了生存时间。对胸肿瘤的免疫组织化学和 Western blot 分析表明，这些药物诱导了细胞周期阻滞、细胞凋亡和肿瘤血管生成抑制。我们的研究结果表明，MEK 和 PI3K 抑制剂的联合治疗是 MPM 的一种有前途的治疗策略。
