2014 - Anticancer Ruthenium(III) Complex KP1019 Interferes with ATP-Dependent Ca2+ Translocation by Sarco-Endoplasmic Reticulum Ca2+-ATPase (SERCA)

  SURFE²R N1 publication in ChemMedChem (2014)

Authors: 
Sadafi F.Z., Massai L., Bartolommei G., Moncelli M.R., Messori L., Tadini-Buoninsegni F.

Journal: 
ChemMedChem. (2014) 9(8):1660-4

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 tocancer 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.

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