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

• Published in: Drug metabolism and disposition Vol. 37; no. 3; pp. 619 - 628
• Main Authors: MINEMATSU, Tsuyoshi, IWAI, Megumi, SUGIMOTO, Kenji, SHIRAI, Nobuaki, NAKAHARA, Takahito, USUI, Takashi, KAMIMURA, Hidetaka
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.03.2009
• Subjects: Animals; Biological and medical sciences; Carbon Radioisotopes - pharmacokinetics; Cell Line, Tumor; Drug Carriers; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Inhibitor of Apoptosis Proteins; Lymphoma - metabolism; Lymphoma - pathology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Microtubule-Associated Proteins - antagonists & inhibitors; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Naphthoquinones - administration & dosage; Naphthoquinones - pharmacokinetics; Naphthoquinones - pharmacology; Neoplasms - metabolism; Neoplasms - pathology; Pharmacology. Drug treatments; Tumors; Human; Solid tumor; Apoptosis inhibitory protein; Malignant tumor; Small molecule; Survivin; Uptake; Tumor cell; Cancer
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.108.025254

1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1 H -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 [ 14 C]YM155 to PC-3-xenografted nude mice revealed a relatively high level of radioactivity in the PC-3 xenograft. Therefore, the uptake of [ 14 C]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 [ 14 C]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 [ 14 C]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 [ 14 C]YM155 to a similar extent among the five cell lines. The half-maximal inhibitory concentration values (IC 50 ) of several compounds for the uptake of [ 14 C]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.