JBIC Journal of Biological Inorganic Chemistry ( IF 2.7 ) Pub Date : 2021-09-21 , DOI: 10.1007/s00775-021-01905-4 Andjelka M Isakovic 1 , Mirjana B Čolović 2 , Tian Ma 3 , Xiang Ma 3 , Marija Jeremic 1 , Marko Gerić 4 , Goran Gajski 4 , Sonja Misirlic-Dencic 1 , Ulrich Kortz 3 , Danijela Krstić 5
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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 PbPd12, previously confirmed promising antileukemic agents, did not exhibit cytogenotoxicity to HPBCs, and thus could be regarded as tumor cell specific and selective drug candidates.
Graphic abstract
中文翻译：
选定的聚氧钯酸盐作为有希望和选择性的抗肿瘤候选药物
多金属氧酸盐（PONMs）是一类结合了多金属氧酸盐和贵金属特性的分子贵金属-氧纳米簇，是开发下一代抗肿瘤金属药物的有前景的平台。本研究旨在评估五种聚氧钯酸盐 (II) 对人类神经母细胞瘤细胞 (SH-SY5Y) 的抗肿瘤潜力以及对健康人类外周血细胞 (HPBCs) 的毒性：(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 )和Na 12 [PbO 8 Pd 12 (PO 4 ) 8 ]·38H 2 O ( PbPd 12))，作为 PONM 的最大子集。纯无机物Pd 13被发现是最有效和选择性最强的抗神经母细胞瘤药物，24 小时和 48 小时的 IC 50值 (µM) 分别为 7.2 ± 2.2 和 4.4 ± 1.2，甚至低于顺铂 (28.4 ± 7.4 和11.6±0.8)。用SrPd 12和Pd 13 L处理 24/48 小时获得的 IC 50值 (µM)分别为 75.8 ± 6.7/76.7 ± 22.9 和 63.8 ± 3.6/21.4 ± 10.8，而SnPd 12和PbPd 12没有显着影响SH-SY5Y 活力( IC 50 > > 100 µM)。钯13在超氧离子过度产生之前引起线粒体内膜去极化，随后是半胱天冬酶激活、DNA 断裂和细胞周期停滞，这些都是凋亡细胞死亡的标志，并伴随着酸性囊泡含量的增加，提示自噬诱导。重要的是， Pd 13在对正常 HPBC 无细胞毒性的浓度下表现出抗肿瘤作用。相反，浓度≥ 1/3 IC 50 (24 h) 的SrPd 12和Pd 13 L降低了 HPBC 的活力，并将尾 DNA 百分比分别提高了 42% 和 3.05 倍，与对照相关。SnPd 12和PbPd 12， 先前证实有前景的抗白血病药物对 HPBC 没有细胞毒性，因此可被视为肿瘤细胞特异性和选择性的候选药物。
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