title: Anticancer ruthenium(III) complex KP1019 interferes with ATP-dependent Ca2+ translocation by sarco-endoplasmic reticulum Ca2+-ATPase (SERCA).
abstract: 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.
authors.affiliation: 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).
authors.forename: Fabrizio-Zagros
authors.initials: FZ
authors.lastname: Sadafi
authors.forename: Lara
authors.initials: L
authors.lastname: Massai
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bartolommei
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Moncelli
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.forename: Francesco
authors.initials: F
authors.lastname: Tadini-Buoninsegni
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism; D000081007:Cymenes; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D007191:Indazoles / Q000737:chemistry* / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017975:Ruthenium Compounds; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D000081007:Cymenes; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C530402:dichloro(4-cymene)(1,3,5-triaza-7-phosphatricyclo(3.3.1.1)decane)ruthenium(II); C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); D000255:Adenosine Triphosphate; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002945:Cisplatin; D002118:Calcium; D004121:Dimethyl Sulfoxide
keywords: ATPase inhibitors; SERCA; anticancer drugs; metallodrugs; sarco-endoplasmic reticulum Ca2+-ATPase; solid-supported membrane