A newly synthesized nickel chelate can selectively target and overcome multidrug resistance in cancer through redox imbalance both in vivo and in vitro
A newly synthesized nickel chelate can selectively target and overcome multidrug resistance in cancer through redox imbalance both in vivo and in vitro
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DOI：
10.1007/s00775-017-1498-4
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发表时间：
2017-12-01
影响因子：
3
通讯作者：
Choudhuri, Soumitra Kumar
中科院分区：
文献类型：
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作者：
Banerjee, Kaushik;Biswas, Manas Kumar;Choudhuri, Soumitra Kumar
不良毒性的诱导和多药耐药(MDR)的出现是癌症治疗的主要障碍。此外，侵袭性癌症对现有化疗药物不太敏感。因此，在不引起不良副作用的情况下选择性靶向肿瘤并设计适当的策略来克服MDR在现代化疗中具有极其重要的意义。以前我们已经揭示了一些席夫碱过渡金属络合物的抗癌性能，但镍配合物的有效性仍未揭示。在此，我们合成了席夫碱镍螯合物N-(2-羟基苯乙酮)甘氨酸镍(Ning)，并通过不同的光谱手段对其进行了表征。Ning被证明是一种广谱抗癌药物，在克服癌症多药耐药方面具有相当的疗效。用耐药细胞(CEM/ADR5000；NIH-MDR-G185；EAC/Dox)、药物敏感的侵袭性细胞(HCT116；CCRF-CEM；EAC/S)和正常细胞(NIH-3T3)评价宁的抗增殖作用，揭示了宁对耐药和敏感癌细胞的选择性，而对正常细胞没有明显的毒性。此外，Ning还参与了活性氧(ROS)介导的氧化还原失衡，通过破坏线粒体膜电位诱导侵袭性药物敏感的HCT116和耐药的NIH-MDR-G185细胞中依赖于caspase 3的细胞凋亡。此外，腹膜腔内(I.P.)应用无毒剂量的宁可显著延长携带敏感和耐阿霉素艾氏腹水癌细胞亚系的瑞士白化小鼠的寿命。值得注意的是，在体外，Ning只能克服P-糖蛋白介导的MDR，而在体内，Ning可以克服MRP1介导的肿瘤多药耐药。因此，Ning具有靶向和克服癌症多药耐药的治疗潜力。
Induction of undesired toxicity and emergence of multidrug resistance (MDR) are the major obstacles for cancer treatment. Moreover, aggressive cancers are less sensitive towards existing chemotherapeutics. Therefore, selective targeting of cancers without inducing undesired side effects and designing proper strategies to overcome MDR has utmost importance in modern chemotherapy. Previously we revealed the anticancer properties of some transition metal chelates of Schiff base, but the effectiveness of nickel complex is still unrevealed. Herein, we synthesized and characterized a Schiff base nickel chelate, nickel-(II) N-(2-hydroxyacetophenone) glycinate (NiNG), through different spectroscopic means. NiNG proves to be a broad spectrum anticancer agent with considerable efficacy to overcome MDR in cancer. Antiproliferative effects of NiNG was evaluated using drug-resistant (CEM/ADR5000; NIH-MDR-G185; EAC/Dox), drug-sensitive aggressive (Hct116; CCRF-CEM; EAC/S) and normal (NIH-3T3) cells that reveal the selective nature of NiNG towards drug resistant and sensitive cancer cells without inducing any significant toxicity in normal cells. Moreover, NiNG involves reactive oxygen species (ROS)-mediated redox imbalance for induction of caspase 3-dependent apoptosis in aggressive drug-sensitive Hct116 and drug-resistant NIH-MDR-G185 cells through disruption of mitochondrial membrane potential. Moreover, intraperitoneal (i.p.) application of NiNG at non-toxic doses caused significant increase in the life-span of Swiss albino mice bearing sensitive and doxorubicin-resistant subline of Ehrlich ascites carcinoma cells. It is noteworthy that, in vitro NiNG can only overcome P-glycoprotein-mediated MDR while in vivo NiNG can overcome MRP1-mediated MDR in cancer. Therefore, NiNG has therapeutic potential to target and overcome MDR in cancer.