Watanabe Saiichiro, Nishijima Nozomi, Hirai Kaho, Shibata Kaoru, Hase Akane, Yamanaka Tsuyoshi, Inazu Masato
Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
Department of Molecular Preventive Medicine, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
Pharmaceuticals (Basel). 2020 May 25;13(5):104. doi: 10.3390/ph13050104.
Choline transporter-like protein 1 (CTL1) is highly expressed in glioma cells, and inhibition of CTL1 function induces apoptotic cell death. Therefore, CTL1 is a potential target molecule for glioma therapy. Here, we investigated the therapeutic mechanism underlying the antitumor effects of Amb4269951, a recently discovered novel CTL1 inhibitor, in the human glioma cell line U251MG, and evaluated its in vivo effects in a mouse xenograft model. Amb4269951 inhibited choline uptake and cell viability and increased caspase-3/7 activity. CTL1-mediated choline uptake is associated with cell viability, and the functional inhibition of CTL1 by Amb4269951 may promote apoptotic cell death via ceramide-induced suppression of the expression of survivin, an apoptotic inhibitory factor. Finally, Amb4269951 demonstrated an antitumor effect in a mice xenograft model by significantly inhibiting tumor growth without any weight loss. Amb4269951 is the lead compound in the treatment of glioma and exhibits a novel therapeutic mechanism. These results may lead to the development of novel anticancer drugs targeting the choline transporter CTL1, which has a different mechanism of action than conventional anticancer drugs against gliomas.
胆碱转运体样蛋白1（CTL1）在胶质瘤细胞中高表达，抑制CTL1功能可诱导细胞凋亡。因此，CTL1是胶质瘤治疗的潜在靶分子。在此，我们研究了最近发现的新型CTL1抑制剂Amb4269951对人胶质瘤细胞系U251MG抗肿瘤作用的治疗机制，并在小鼠异种移植模型中评估了其体内效应。Amb4269951抑制胆碱摄取和细胞活力，并增加caspase-3/7活性。CTL1介导的胆碱摄取与细胞活力相关，Amb4269951对CTL1的功能抑制可能通过神经酰胺诱导凋亡抑制因子survivin表达的抑制来促进细胞凋亡。最后，Amb4269951在小鼠异种移植模型中通过显著抑制肿瘤生长且无体重减轻表现出抗肿瘤作用。Amb4269951是治疗胶质瘤的先导化合物，具有新的治疗机制。这些结果可能会推动针对胆碱转运体CTL1的新型抗癌药物的研发，其作用机制与传统抗胶质瘤抗癌药物不同。
