Sadafi Fabrizio-Zagros, Massai Lara, Bartolommei Gianluca, Moncelli Maria Rosa, Messori Luigi, Tadini-Buoninsegni Francesco
Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino (Italy); Institute of Particle Technology, University of Erlangen-Nuremberg, 91058 Erlangen (Germany).
ChemMedChem. 2014 Aug;9(8):1660-4. doi: 10.1002/cmdc.201402128. Epub 2014 Jun 11.
Sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), a P-type ATPase that sustains Ca2+ transport and plays a major role in intracellular Ca2+ homeostasis, represents a therapeutic target for cancer therapy. Here, we investigated whether ruthenium-based anticancer drugs, namely KP1019 (indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)]), NAMI-A (imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)]) and RAPTA-C ([Ru(η6-p-cymene)dichloro(1,3,5-triaza-7-phosphaadamantane)]), and cisplatin (cis-diammineplatinum(II) dichloride) might act as inhibitors of SERCA. Charge displacement by SERCA adsorbed on a solid-supported membrane was measured after ATP or Ca2+ concentration jumps. Our results show that KP1019, in contrast to the other metal compounds, is able to interfere with ATP-dependent translocation of Ca2+ ions. An IC50 value of 1 μM was determined for inhibition of calcium translocation by KP1019. Conversely, it appears that KP1019 does not significantly affect Ca2+ binding to the ATPase from the cytoplasmic side. Inhibition of SERCA at pharmacologically relevant concentrations may represent a crucial aspect in the overall pharmacological and toxicological profile of KP1019.
肌质网钙-ATP酶（SERCA）是一种P型ATP酶，可维持钙离子运输并在细胞内钙离子稳态中起主要作用，是癌症治疗的一个靶点。在此，我们研究了钌基抗癌药物，即KP1019（吲唑盐[反式-四氯双(1H-吲唑)钌(III)]）、NAMI-A（咪唑盐[反式-四氯(1H-咪唑)(S-二甲亚砜)钌(III)]）和RAPTA-C（[Ru(η6-对异丙基苯)二氯(1,3,5-三氮杂-7-磷杂金刚烷)]）以及顺铂（顺式-二氨合铂(II)二氯化物）是否可能作为SERCA的抑制剂。在ATP或钙离子浓度跃升后，测量吸附在固体支持膜上的SERCA的电荷位移。我们的结果表明，与其他金属化合物不同，KP1019能够干扰钙离子的ATP依赖性转运。测定出KP1019抑制钙离子转运的IC50值为1 μM。相反，似乎KP1019不会显著影响钙离子从细胞质一侧与ATP酶的结合。在药理学相关浓度下抑制SERCA可能是KP1019整体药理学和毒理学特性的一个关键方面。
