Abstract
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.
Highlights
Primary brain tumors are very diverse, and the WHO classification categorizes them into approximately 150 types according to various characteristics
We examined the effects of Amb4269951 (Figure 1) and the choline uptake inhibitor, HC-3, on
PCho is a precursor of PC, a major component of the cell membrane that is and the rate-limiting step of the choline The metabolic system, and is into mediated byisthe transporter
Summary
Primary brain tumors are very diverse, and the WHO classification categorizes them into approximately 150 types according to various characteristics. Gliomas are the most common type of malignant brain tumor, accounting for 25% of all cases. The occurrence of gliomas is rare, their prognosis is extremely poor, with the 5-year survival rate of glioblastoma (grade IV). Very few antitumor drugs are available for treating gliomas. Some cases are difficult to treat due to the emergence of resistance to the alkylating agent temozolomide, which has otherwise demonstrated effectiveness [3,4,5]. Since most of the other available anticancer agents for treating gliomas are alkylating agents, there is a need for alternatives based on novel therapeutic mechanisms
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