Anticancer Ruthenium(III) Complex KP1019 Interferes with ATP‐Dependent Ca 2+ Translocation by Sarco‐Endoplasmic Reticulum Ca 2+ ‐ATPase (SERCA)

Sarco‐endoplasmic reticulum Ca 2+ ‐ATPase (SERCA), a P‐type ATPase that sustains Ca 2+ transport and plays a major role in intracellular Ca 2+ homeostasis, represents a therapeutic target for cancer therapy. Here, we investigated whether ruthenium‐based anticancer drugs, namely KP1019 (indazolium [ trans ‐tetrachlorobis(1 H ‐indazole)ruthenate(III)]), NAMI‐A (imidazolium [ trans ‐tetrachloro(1 H ‐imidazole)( S ‐dimethylsulfoxide)ruthenate(III)]) and RAPTA‐C ([Ru(η 6 ‐ 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 Ca 2+ concentration jumps. Our results show that KP1019, in contrast to the other metal compounds, is able to interfere with ATP‐dependent translocation of Ca 2+ ions. An IC 50 value of 1 μ M was determined for inhibition of calcium translocation by KP1019. Conversely, it appears that KP1019 does not significantly affect Ca 2+ 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.