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Anticancer Ruthenium(III) Complex KP1019 Interferes with ATP‐Dependent Ca2+ Translocation by Sarco‐Endoplasmic Reticulum Ca2+‐ATPase (SERCA)
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AbstractSarco‐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.
Title: Anticancer Ruthenium(III) Complex KP1019 Interferes with ATP‐Dependent Ca2+ Translocation by Sarco‐Endoplasmic Reticulum Ca2+‐ATPase (SERCA)
Description:
AbstractSarco‐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.
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