Selected polyoxopalladates as promising and selective antitumor drug candidates

Andjelka M Isakovic; Mirjana B Čolović; Tian Ma; Xiang Ma; Marija Jeremic; Marko Gerić; Goran Gajski; Sonja Misirlic-Dencic; Ulrich Kortz; Danijela Krstić

doi:10.1007/s00775-021-01905-4

Selected polyoxopalladates as promising and selective antitumor drug candidates

J Biol Inorg Chem. 2021 Dec;26(8):957-971. doi: 10.1007/s00775-021-01905-4. Epub 2021 Sep 21.

Authors

Affiliations

¹ Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
² Department of Physical Chemistry, "Vinča" Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
³ Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany.
⁴ Institute for Medical Research and Occupational Health, Mutagenesis Unit, Zagreb, Croatia.
⁵ Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. sonja.misirlic-dencic@med.bg.ac.rs.
⁶ Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany. u.kortz@jacobs-university.de.
⁷ Institute of Medical Chemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. danijela.krstic@med.bg.ac.rs.

PMID: 34549367
DOI: 10.1007/s00775-021-01905-4

Abstract

Polyoxo-noble-metalates (PONMs), a class of molecular noble metal-oxo nanoclusters that combine features of both polyoxometalates and noble metals, are a promising platform for the development of next-generation antitumor metallodrugs. This study aimed to evaluate the antitumor potential against human neuroblastoma cells (SH-SY5Y), as well as toxicity towards healthy human peripheral blood cells (HPBCs), of five polyoxopalladates(II): (Na₈[Pd₁₃As₈O₃₄(OH)₆]·42H₂O (Pd₁₃), Na₄[SrPd₁₂O₆(OH)₃(PhAsO₃)₆(OAc)₃]·2NaOAc·32H₂O (SrPd₁₂), Na₆[Pd₁₃(AsPh)₈O₃₂]·23H₂O (Pd₁₃L), Na₁₂[SnO₈Pd₁₂(PO₄)₈]·43H₂O (SnPd₁₂), and Na₁₂[PbO₈Pd₁₂(PO₄)₈]·38H₂O (PbPd₁₂)), as the largest subset of PONMs. A pure inorganic, Pd₁₃, was found as the most potent and selective antineuroblastoma agent with IC₅₀ values (µM) of 7.2 ± 2.2 and 4.4 ± 1.2 for 24 and 48 h treatment, respectively, even lower than cisplatin (28.4 ± 7.4 and 11.6 ± 0.8). The obtained IC₅₀ values (µM) for 24/48 h treatment with SrPd₁₂ and Pd₁₃L were 75.8 ± 6.7/76.7 ± 22.9 and 63.8 ± 3.6/21.4 ± 10.8, respectively, whereas SnPd₁₂ and PbPd₁₂ did not remarkably affect the SH-SY5Y viability (IC₅₀ > > 100 µM). Pd₁₃ caused depolarisation of inner mitochondrial membrane prior to superoxide ion hyperproduction, followed by caspase activation, DNA fragmentation and cell cycle arrest, all hallmarks of apoptotic cell death, and accompanied by an increase in acidic vesicles content, suggestive of autophagy induction. Importantly, Pd₁₃ demonstrated the antitumor effect at concentrations not cytogenotoxic for normal HPBCs. On the contrary, SrPd₁₂ and Pd₁₃L at concentrations ≥ 1/3 IC₅₀(24 h) decreased HPBC viability and increased % tail DNA up to 42% and 3.05 times, respectively, related to control. SnPd₁₂ and PbPd_12, previously confirmed promising antileukemic agents, did not exhibit cytogenotoxicity to HPBCs, and thus could be regarded as tumor cell specific and selective drug candidates.

Keywords: Antitumor; Cytogenotoxicity; Human neuroblastoma cells (SH-SY5Y); Human peripheral blood cells; Polyoxopalladates.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Apoptosis
Cell Line, Tumor
Cell Survival
Cisplatin / pharmacology
Humans
Neuroblastoma* / drug therapy

Substances

Antineoplastic Agents
Cisplatin