Banerjee Kaushik, Biswas Manas Kumar, Choudhuri Soumitra Kumar
Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, 700 026, India.
Department of Chemistry, Ramakrishna Mission Residential College, Kolkata, India.
J Biol Inorg Chem. 2017 Dec;22(8):1223-1249. doi: 10.1007/s00775-017-1498-4. Epub 2017 Oct 23.
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.
产生不良毒性和多药耐药性（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的敏感性较低。因此，在现代化疗中，选择性靶向癌症而不引起不良副作用并设计适当策略来克服MDR至关重要。此前我们揭示了一些席夫碱过渡金属螯合物的抗癌特性，但镍配合物的有效性仍未明确。在此，我们通过不同的光谱手段合成并表征了一种席夫碱镍螯合物，即镍 -（II）N -（2 - 羟基苯乙酮）甘氨酸酯（NiNG）。NiNG被证明是一种广谱抗癌剂，在克服癌症中的MDR方面具有相当的疗效。使用耐药（CEM/ADR5000；NIH - MDR - G185；EAC/Dox）、药物敏感的侵袭性（Hct116；CCRF - CEM；EAC/S）和正常（NIH - 3T3）细胞评估了NiNG的抗增殖作用，结果表明NiNG对耐药和敏感癌细胞具有选择性，且对正常细胞无明显毒性。此外，NiNG通过破坏线粒体膜电位，在侵袭性药物敏感的Hct116细胞和耐药的NIH - MDR - G185细胞中，涉及活性氧（ROS）介导的氧化还原失衡，从而诱导半胱天冬酶3依赖性凋亡。此外，以无毒剂量腹腔注射NiNG可显著延长携带艾氏腹水癌细胞敏感和多柔比星耐药亚系的瑞士白化小鼠的寿命。值得注意的是，体外NiNG只能克服P - 糖蛋白介导的MDR，而体内NiNG可以克服癌症中MRP1介导的MDR。因此，NiNG具有靶向和克服癌症中MDR的治疗潜力。
