title: Intracellular uptake of an antitumor-active azole-bridged dinuclear platinum(II) complex in cisplatin-resistant tumor cells.
abstract: A cationic azolato-bridged dinuclear platinum(II) complex, [{cis-Pt(NH3)2}2(μ-OH)(μ-methyl-pyrazolate)]2+(4M-PzPt), was developed to overcome resistance to cisplatin (CDDP). This study aimed to assess the cytotoxicity of 4M-PzPt against a CDDP-resistant cell line, H4-II-E/CDDP, and compare the intracellular accumulation of CDDP and 4M-PzPt. H4-II-E and H4-II-E/CDDP displayed similar sensitivity to 4M-PzPt; however, the sensitivity of H4-II-E/CDDP to CDDP was approximately 19-fold lower than that of H4-II-E. The difference in the sensitivity to both platinum complexes corresponded with the difference in the amount of intracellular platinum accumulation after exposure to CDDP or 4M-PzPt in both cell lines. In H4-II-E, HepG2, and HuH-7 cells, the intracellular uptake of CDDP and 4M-PzPt occurred via active transport and passive transport. Results of co-exposure with the transport inhibitors ouabain, tetraethylammonium, and cimetidine indicated that the intracellular uptake of CDDP was dependent on Na+/K+-ATPase and that of 4M-PzPt was dependent on organic cation transporters (OCTs), probably OCT1. This study suggested that 4M-PzPt could inhibit the growth of a CDDP-resistant tumor via an intracellular uptake mechanism different from that of CDDP.
authors: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima 1-1-3, Chuo-ku, Kobe, 650-8586, Japan. skisimot@pharm.kobegakuin.ac.jp.
authors: Shuichi
authors: 0000-0001-9061-5743
authors: S
authors: Kishimoto
authors: Department of Pharmacy, Shool of Pharmacy, Hyogo University of Helth Sciences, Minatojima 1-3-6, Chuo-ku, Kobe, 650-8530, Japan.
authors: Megumi
authors: M
authors: Yasuda
authors: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima 1-1-3, Chuo-ku, Kobe, 650-8586, Japan.
authors: Ryosuke
authors: R
authors: Suzuki
authors: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima 1-1-3, Chuo-ku, Kobe, 650-8586, Japan.
authors: Shoji
authors: S
authors: Fukushima
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001393:Azoles / Q000737:chemistry; D045744:Cell Line, Tumor; D002927:Cimetidine / Q000494:pharmacology; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010042:Ouabain / Q000494:pharmacology; D010984:Platinum / Q000493:pharmacokinetics; D051381:Rats; D013696:Temperature; D019789:Tetraethylammonium / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001393:Azoles; D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; D010984:Platinum; D010042:Ouabain; D019789:Tetraethylammonium; D002927:Cimetidine; D002945:Cisplatin
keywords: Cancer; Cisplatin; Platinum; Resistance; Transporter