Bromide ( YM 155 Monobromide ) , a Novel , Small Molecule Survivin Suppressant

1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide), which is a hydrophilic and cationic compound, exhibits antitumor activity in experimental human hormone refractory prostate carcinoma models. Urinary excretion was 18.3 to 28.6% of the dose in the clinical phase I study, and nonrenal elimination may be explained by the biliary excretion of YM155 in its unchanged form. Because the penetration through the sinusoidal membrane of the hepatocytes is the first step and an important part of biliary excretion, we evaluated the uptake of [C]YM155 into human cryopreserved hepatocytes. YM155 was taken up into hepatocytes in a temperatureand concentration-dependent manner. The saturable uptake component was much higher than the nonsaturable passive diffusion component. In vitro hepatic uptake clearance was consistent with the in vivo hepatic intrinsic clearance calculated using clinical study data. Hepatic uptake of YM155 was inhibited by organic cation transporter (OCT) inhibitors, and the IC50 values for YM155 uptake were comparable to those reported for human OCT1-mediated transport. The interaction of YM155 with candidate transporter, OCT1, was also characterized using S2 cells stably expressing human OCT1 (OCT1-S2) cells. In OCT1-expressing S2 cells, YM155 inhibited the OCT1-mediated uptake of a typical OCT1 substrate, [C]tetraethylammonium. In addition, YM155 was taken up into OCT1-S2 cells These results indicated that OCT1 was the predominant transporter for the hepatic uptake of YM155, and the transporter-mediated uptake clearance observed in vitro may account for the in vivo intrinsic hepatic clearance. Increasing evidence suggests that survivin, a member of the inhibitor of apoptosis protein family, is an essential regulator of cell division and a modulator of apoptotic cell death (Ambrosini et al., 1997; O’Connor et al., 2000; Giodini et al., 2002; Altieri, 2006). Survivin is abundantly expressed during fetal development, but its expression is absent or low in most adult human differentiated tissues, with the exception of rapidly proliferating or self-renewing tissues. Survivin has been found to be overexpressed in various kinds of tumor tissues (Ambrosini et al., 1997; O’Driscoll et al., 2003), suggesting that survivin may be an attractive, novel target for cancer chemotherapy with the dual aim of preventing cancer cell proliferation and enhancing the cancer cell-selective response to apoptosis. 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 small molecule that specifically inhibits survivin gene transcription and protein expression in several tumor cell lines (Nakahara et al., 2007). During a phase I clinical study, YM155 exhibited antitumor activity in some patients with non-Hodgkin’s lymphoma, hormone refractory prostate cancer, and non–small-cell lung cancer Parts of this work were previously presented in abstract form as follows: Iwai M, Minematsu T, Usui T, and Kamimura H (2007) Characterization of the carriermediated hepatic uptake of YM155, a novel survivin suppressant, into cryopreserved human hepatocytes. 8th International ISSX Meeting; 2007 Oct 9–12; Sendai, Japan. International Society for the Study of Xenobiotics, Washington,