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.

Abstract

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 [(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 microM). 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.

• Authors: Tsuyoshi Minematsu, Megumi Iwai, Kenji Sugimoto, Nobuaki Shirai, Takahito Nakahara, Takashi Usui, Hidetaka Kamimura
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 37 Issue 3 Pg. 619-28 (Mar 2009) ISSN: 1521-009X [Electronic] United States
• PMID: 19056913 (Publication Type: Journal Article)

Chemical References

• BIRC5 protein, human
• Carbon Radioisotopes
• Drug Carriers
• Imidazoles
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Naphthoquinones
• Survivin
• sepantronium

Topics

• Animals
• Carbon Radioisotopes (pharmacokinetics)
• Cell Line, Tumor
• Drug Carriers
• Humans
• Imidazoles (administration & dosage, pharmacokinetics, pharmacology)
• Inhibitor of Apoptosis Proteins
• Lymphoma (metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microtubule-Associated Proteins (antagonists & inhibitors)
• Naphthoquinones (administration & dosage, pharmacokinetics, pharmacology)
• Neoplasms (metabolism, pathology)
• Survivin