Short Communication Characterization of Human Organic Cation Transporter 1 (OCT1/SLC22A1)- and OCT2 (SLC22A2)-Mediated Transport 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

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 human hormone refractory prostate carcinoma cell line PC-3. Although YM155, which has a cationic moiety in its structure, is influxed into its pharmacologically effective site (cancer cells) and one of its eliminating organs (hepatocytes) in a transporter-mediated manner, the mechanism seems to be different between the two cell types. The other eliminating organ is the kidney. In this study, the transport of [C]YM155 was characterized by using human embryonic kidney 293 cells expressing organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). YM155 inhibited the uptake of a typical substrate [H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC50 values of 23.8, 15.9, and 108 M, respectively. The timeand saturable concentration-dependent uptake of [C]YM155 was observed in cells expressing OCT1 and OCT2 with Km values of 22.1 and 2.67 M, respectively, but not in cells expressing OCT3. By taking into consideration the tissue distribution and localization of each transporter, these results suggest that, in humans, YM155 is taken up from the blood into hepatocytes and proximal tubular cells via OCT1 and OCT2, respectively. The comparison of the IC50 values of OCT inhibitors and Km values for the uptake of YM155 into cells expressing OCTs with those into cancer cell lines indicated that transporter(s) other than OCT1 and OCT2 are involved in the uptake of YM155 into cancer cell lines. Survivin is a member of the inhibitors of apoptosis family proteins that has been implicated in both the preservation of cell viability and the regulation of mitosis in tumor cells (Ambrosini et al., 1997; O’Connor et al., 2000; Giodini et al., 2002). Given its preferential expression in tumor cells, its ability to block apoptosis and regulate cancer cell proliferation, and its correlation with poor survival, survivin seems to be a novel target for cancer therapy (Nakahara et al., 2007). 1-(2-Methoxyethyl)-2-methyl-4,9-dioxo3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide) (Fig. 1) inhibits survivin expression in tumor cells and has an inhibitory effect on cell growth in various human cancer cell lines (Nakahara et al., 2007). Moreover, in nude mice bearing human hormone refractory prostate cancer PC-3 tumor, 3-day continuous subcutaneous infusion of YM155 (3–10 mg/kg) induced tumor regression accompanied by the suppression of intratumoral survivin (Nakahara et al., 2007). In a phase I study conducted in the United States, YM155 exhibited some pharmacological effects in non-Hodgkin’s lymphoma, hormone refractory prostate cancer, and patients with non-small cell lung cancer (Tolcher et al., 2008). It is possible that the major elimination route of YM155 is excretion via urine and bile in the unchanged form. During intravenous continuous infusion in this phase I study, 18.3 to 28.6% of the dose was excreted into urine as unchanged YM155 (Tolcher et al., 2008). By using the parameters reported by Tolcher et al. (2008), renal clearance at dose level of 3.6 to 4.8 mg/m/day is estimated to be approximately 17 to 19 l/h at the dose, which is Parts of this work were previously presented in abstract form follows: Minematsu T, Iwai M, Umehara K, Usui T, and Kamimura H (2007) Human organic cation transporter 1-mediated transport of YM155, a novel survivin suppressant. 8th International ISSX Meeting 2007; 2007 Oct 9–12; Sendai, Japan. Drug Metab Rev 39 (Suppl 1):67; Iwai M, Minematsu T, Umehara K, Usui T, and Kamimura H (2008) Role of organic cation transporter 1 (OCT1), OCT2, and OCT3 in the pharmacokinetics of YM155, a novel survivin suppressant. 15th North American ISSX Meeting 2008; 2008 Oct 12–16; San Diego, CA. Drug Metab Rev 40 (Suppl