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Carrier-Mediated Uptake of 1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium Bromide (YM155 Monobromide), a Novel Small-Molecule Survivin Suppressant, into Human Solid Tumor and Lymphoma Cells

Drug Metabolism Research Laboratories (T.M., M.I., T.U., H.K.) and Project Management Department (T.N.), Astellas Pharma Inc., Tokyo, Japan; Mitsubishi Chemical Safety Institute, Ltd., Kumamoto, Japan (K.S.); and Nemoto Science Co., Ltd., Ibaraki, Japan (N.S.)

1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide) is a novel small-molecule survivin suppressant that induces the down-regulation of survivin and exhibits potent antitumor activity in nude mice bearing the human hormone refractory prostate carcinoma cell line PC-3. In this study, radioluminographic determination of the in vivo distribution of radioactivity after administration of [¹⁴C]YM155 to PC-3-xenografted nude mice revealed a relatively high level of radioactivity in the PC-3 xenograft. Therefore, the uptake of [¹⁴C]YM155 was further characterized in vitro using PC-3, lung cancer (Calu-6 and NCI-H358), malignant melanoma (A375 and SK-MEL-5), and non-Hodgkin's lymphoma (RL and Ramos) cell lines. The uptake of [¹⁴C]YM155 in these cell lines was dependent on incubation time, temperature, and drug concentration. The Michaelis-Menten constant values were similar among the seven cell lines (0.189–0.367 µM). The effects of various compounds on the uptake of [¹⁴C]YM155 were tested in PC-3, Calu-6, A375, RL, and Ramos cell lines. Of the compounds tested, the cationic transporter substrates/inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridium, cimetidine, prazosin, corticosterone, verapamil, amantadine, procainamide, and N-methylnicotinamide) inhibited the uptake of [¹⁴C]YM155 to a similar extent among the five cell lines. The half-maximal inhibitory concentration values (IC₅₀) of several compounds for the uptake of [¹⁴C]YM155 into PC-3 differed from those reported in the literature for human organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). To summarize, YM155 was taken up into cancer cells in a carrier-mediated manner and with a similar affinity among all the cancer cell lines tested. An influx transporter(s) may contribute to this process.

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				M. Iwai, T. Minematsu, S. Narikawa, T. Usui, and H. Kamimura Involvement of Human Organic Cation Transporter 1 in the Hepatic Uptake of 1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium Bromide (YM155 Monobromide), a Novel, Small Molecule Survivin Suppressant Drug Metab. Dispos., September 1, 2009; 37(9): 1856 - 1863. [Abstract] [Full Text] [PDF]