Anticancer Activity of Amb4269951, a Choline Transporter-Like Protein 1 Inhibitor, in Human Glioma Cells

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.

Molecular and Functional Analysis of Choline Transporters and Antitumor Effects of Choline Transporter-Like Protein 1 Inhibitors in Human Pancreatic Cancer Cells

“…The inhibitory effect of Amb4269951 and Amb4269675 on cell viability was enhanced in a treatment-time-dependent manner. Time-dependent suppression of cell viability by Amb4269951 was also observed in U251MG glioma cells [20]. These effects of both compounds may be due to the inhibition of choline uptake, which inhibits choline metabolic systems, including the Kennedy pathway, and thus suppresses phospholipid synthesis in the cell membrane.…”

“…Recently, we discovered isoquinoline derivative Amb4269951 and its derivative, Amb4269675, from a library of plant-derived natural organic compounds during the search for compounds that inhibit both CTL1-mediated choline uptake and cell viability in MIA PaCa-2 cells [19]. We reported that Amb4269951 causes apoptosis-induced cell death in human glioma cells by suppressing the expression of apoptosis inhibitor survivin through the production of ceramide caused by CTL1-mediated inhibition of choline uptake [20]. However, neither Amb4269951 nor Amb4269675 have been studied in pancreatic-cancer cells.…”

“…Both Amb4269951 ( Figure 7C) and Amb4269675 ( Figure 7D) significantly inhibited cell viability and significantly increased caspase-3/7 activity in a concentration-dependent manner. Since Amb4269951 was reported to enhance caspase-3/7 activity and suppress cell viability in glioma cells [20], we examined these effects of Amb4269951 and Amb4269675 in MIA PaCa-2 cells. Both Amb426951 and Amb4269675 inhibited cell viability in a concentration-dependent manner, and their effects were enhanced in a treatment-time-dependent manner ( Figure 7A,B).…”

“…Therefore, we searched for compounds that inhibit both CTL1-mediated choline uptake and cell viability in human pancreatic-cancer cells from a library of plant-derived natural organic compounds and discovered isoquinoline derivative Amb4269951 and its derivative Amb4269675 [19]. Recent studies suggested that CTL1 inhibition of Amb4269951 in human glioma cells causes apoptosis-induced cell death by suppressing the expression of apoptosis inhibitory factor survivin via the production of apoptosis-inducing molecule ceramide [20]. Thus, although Amb4269951 has a unique mechanism for cancer treatment, this has never been seen before.…”

“…Thus, although Amb4269951 has a unique mechanism for cancer treatment, this has never been seen before. Amb4269951 showed the inhibition of cell viability against various cancer cells, most notably, human pancreatic-cancer cell line MIA PaCa-2 [20]. However, the antitumor effects of both Amb4269951 and Amb4269675 in MIA PaCa-2 cells have not been studied.…”