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Synthesis and Evaluation of a Ruthenium-based Mitochondrial Calcium Uptake Inhibitor
07:12

Synthesis and Evaluation of a Ruthenium-based Mitochondrial Calcium Uptake Inhibitor

Published on: October 26, 2017

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Anticancer ruthenium(III) complex KP1019 interferes with ATP-dependent Ca2+ translocation by sarco-endoplasmic

Fabrizio-Zagros Sadafi1, Lara Massai, Gianluca Bartolommei

  • 1Department 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
|June 13, 2014
PubMed

Insights

Ruthenium-based drug KP1019 inhibits Sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) by interfering with calcium ion transport. This SERCA inhibition at pharmacologically relevant concentrations may impact KP1019

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cancer Therapy

Background:

  • Sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) is crucial for intracellular calcium homeostasis and a potential cancer therapy target.
  • Ruthenium-based anticancer drugs are being explored for novel therapeutic mechanisms.

Purpose of the Study:

  • To investigate the potential of ruthenium-based anticancer drugs (KP1019, NAMI-A, RAPTA-C) and cisplatin as SERCA inhibitors.
  • To determine the mechanism and potency of SERCA inhibition by KP1019.

Main Methods:

  • Utilized charge displacement measurements on SERCA adsorbed on a solid-supported membrane.
  • Performed ATP and Ca2+ concentration jump experiments to assess SERCA activity.
  • Determined IC50 values for inhibition of calcium translocation.

Main Results:

  • KP1019 demonstrated significant inhibition of ATP-dependent Ca2+ translocation by SERCA, with an IC50 of 1 μM.
  • Other metal compounds tested (NAMI-A, RAPTA-C, cisplatin) did not inhibit SERCA.
  • KP1019 did not significantly affect Ca2+ binding to SERCA from the cytoplasmic side.

Conclusions:

  • KP1019 inhibits SERCA by interfering with Ca2+ translocation, distinct from its effect on Ca2+ binding.
  • SERCA inhibition by KP1019 at pharmacologically relevant concentrations is a key factor in its pharmacological and toxicological profile.
  • This finding suggests a novel mechanism of action for KP1019 in cancer therapy.
Keywords:
ATPase inhibitorsSERCAanticancer drugsmetallodrugssarco-endoplasmic reticulum Ca2+-ATPasesolid-supported membrane

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