Selected polyoxopalladates as promising and selective antitumor drug candidates.

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): (Na ₈ [Pd ₁₃ As ₈ O ₃₄ (OH) ₆ ]·42H ₂ O (Pd ₁₃ ), Na ₄ [SrPd ₁₂ O ₆ (OH) ₃ (PhAsO ₃ ) ₆ (OAc) ₃ ]·2NaOAc·32H ₂ O (SrPd ₁₂ ), Na ₆ [Pd ₁₃ (AsPh) ₈ O ₃₂ ]·23H ₂ O (Pd ₁₃ L), Na ₁₂ [SnO ₈ Pd ₁₂ (PO ₄ ) ₈ ]·43H ₂ O (SnPd ₁₂ ), and Na ₁₂ [PbO ₈ Pd ₁₂ (PO ₄ ) ₈ ]·38H ₂ O (PbPd ₁₂ )), as the largest subset of PONMs. A pure inorganic, Pd ₁₃ , was found as the most potent and selective antineuroblastoma agent with IC ₅₀ 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 IC ₅₀ values (µM) for 24/48 h treatment with SrPd ₁₂ and Pd ₁₃ L were 75.8 ± 6.7/76.7 ± 22.9 and 63.8 ± 3.6/21.4 ± 10.8, respectively, whereas SnPd ₁₂ and PbPd ₁₂ did not remarkably affect the SH-SY5Y viability (IC ₅₀  > > 100 µM). Pd ₁₃ 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, Pd ₁₃ demonstrated the antitumor effect at concentrations not cytogenotoxic for normal HPBCs. On the contrary, SrPd ₁₂ and Pd ₁₃ L at concentrations ≥ 1/3 IC ₅₀  (24 h) decreased HPBC viability and increased % tail DNA up to 42% and 3.05 times, respectively, related to control. SnPd ₁₂ 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.
(© 2021. Society for Biological Inorganic Chemistry (SBIC).)