Hayashi Mutsumi, Madokoro Hiroko, Yamada Koji, Nishida Hiroko, Morimoto Chikao, Sakamoto Michiie, Yamada Taketo
Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku 160-8582 Japan ; Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku 160-8582 Japan.
Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku 160-8582 Japan.
Cancer Cell Int. 2016 Apr 30;16:35. doi: 10.1186/s12935-016-0310-9. eCollection 2016.
Malignant Mesothelioma (MM) is a highly aggressive tumor with poor prognosis. Multimodal treatments and novel molecular targeted therapies against MM are in high demand in order treat this disease effectively. We have developed a humanized monoclonal antibody YS110 against CD26 expressed in 85 % of MM cases. CD26 is thought to be involved in tumor growth and invasion by interacting with collagen and fibronectin, or affecting signal transduction processes.
We evaluated the direct anti-tumor effect of YS110 against MM cell lines, NCI-H2452 and JMN, and investigated its effects on cell cycle and on the cell cycle regulator molecules. In addition, we investigated synergistic effects of YS110 and anti-tumor agent pemetrexed (PMX) against MM cell line both in vitro and in vivo.
YS110 suppressed the proliferation of NCI-H2452 cells by approximately 20 % in 48 h. Based on cell cycle analysis, percentage of cells in G2/M phase increased 8.0 % on the average after YS110 treatment; in addition, cell cycle regulator p21 cip/waf1 was increased and cyclin B1 was decreased after YS110 treatment. Inhibitory phosphorylation of both cdc2 (Tyr15) and cdc25C (Ser216) were elevated. Furthermore, activating phosphorylation of p38 MAPK (Thr180/Tyr182) and ERK1/2 (Thr202/Tyr204) were augmented at 24 h after YS110 treatment. PMX rapidly induced CD26 expression on cell surface and the treatment with both YS110 and PMX inhibited in vivo tumor growth accompanied by a synergistic reduction in the MIB-1 index.
This is a first report of a novel anti-proliferative mechanism of the humanized anti-CD26 monoclonal antibody YS110, which resulted in G2/M cell cycle delay through regulation of quantity and activity of various cell cycle regulating molecules.
恶性间皮瘤（MM）是一种侵袭性很强且预后较差的肿瘤。为有效治疗该疾病，对MM的多模式治疗和新型分子靶向治疗的需求很高。我们已研发出一种针对85%的MM病例中表达的CD26的人源化单克隆抗体YS110。CD26被认为通过与胶原蛋白和纤连蛋白相互作用或影响信号转导过程而参与肿瘤生长和侵袭。
我们评估了YS110对MM细胞系NCI-H2452和JMN的直接抗肿瘤作用，并研究了其对细胞周期和细胞周期调节分子的影响。此外，我们在体外和体内研究了YS110与抗肿瘤药物培美曲塞（PMX）对MM细胞系的协同作用。
YS110在48小时内使NCI-H2452细胞的增殖抑制了约20%。基于细胞周期分析，YS110处理后，G2/M期细胞的百分比平均增加了8.0%；此外，YS110处理后细胞周期调节因子p21 cip/waf1增加，细胞周期蛋白B1减少。cdc2（Tyr15）和cdc25C（Ser216）的抑制性磷酸化均升高。此外，在YS110处理24小时后，p38丝裂原活化蛋白激酶（Thr180/Tyr182）和ERK1/2（Thr202/Tyr204）的活化磷酸化增强。PMX可迅速诱导细胞表面CD26的表达，YS110和PMX联合处理可抑制体内肿瘤生长，同时MIB-1指数协同降低。
这是关于人源化抗CD26单克隆抗体YS110新型抗增殖机制的首次报道，该机制通过调节各种细胞周期调节分子的数量和活性导致G2/M细胞周期延迟。
