König Marcel, Siegmund Daniel, Raszeja Lukasz J, Prokop Aram, Metzler-Nolte Nils
Department of Paedriatic Oncology , Children's Hospital Cologne , Amsterdamer Strasse 59 , 50735 Cologne , Germany.
Chair of Inorganic Chemistry I - Bioinorganic Chemistry , Faculty of Chemistry and Biochemistry , Ruhr University Bochum , Universitätsstrasse 150 , D-44801 Bochum , Germany . Email:
Medchemcomm. 2017 Dec 20;9(1):173-180. doi: 10.1039/c7md00545h. eCollection 2018 Jan 1.
Emerging resistances of tumors against multiple anti-cancer agents are a major concern in the chemotherapeutical treatment of various cancers. Clearly, this raises the need for novel therapeutics with new modes of action. Herein, we report on the favorable anti-proliferative properties of a phenanthridine-containing Re(CO) complex (compound , also abbreviated LR-166) and identify major contributions to its mode of action. The complex induces apoptosis in low micromolar concentrations even in drug-resistant Burkitt-like lymphoma (BJAB) and leukemia (Nalm-6) cell lines with known overexpression of -glycoproteins as was confirmed by measuring the amount of hypodiploid DNA FACS Scan analysis. Importantly, a gene expression analysis in combination with toxicity studies on a number of modified cell lines (leukemia: NALM-6, lymphoma: BJAB, melanoma: MelHO) and the reduction of mitochondrial membrane potential (determined by adding JC-1 dye, followed by FACS analysis) confirmed the activation of both, the extrinsic and the intrinsic apoptotic pathway. Finally, the mechanism of action was shown not to be influenced by overexpression of the anti-apoptotic factor Bcl-2 in Mel-HO cells which are known to be resistant to a variety of drugs. All taken together, our experiments underscore the unique opportunities inherent in this novel lead structure of Re complexes to act as an effective chemotherapeutic agent in a combination therapy to overcome documented drug resistances in tumors.
肿瘤对多种抗癌药物产生的新耐药性是各种癌症化疗治疗中的一个主要问题。显然，这就需要具有新作用模式的新型治疗方法。在此，我们报告了一种含菲啶的铼（羰基）配合物（化合物 ，也缩写为LR - 166）具有良好的抗增殖特性，并确定了其作用模式的主要因素。通过FACS扫描分析测量亚二倍体DNA的量证实，该配合物即使在已知存在 -糖蛋白过表达的耐药伯基特样淋巴瘤（BJAB）和白血病（Nalm - 6）细胞系中，在低微摩尔浓度下也能诱导细胞凋亡。重要的是，结合对多种修饰细胞系（白血病：NALM - 6，淋巴瘤：BJAB，黑色素瘤：MelHO）的毒性研究进行的基因表达分析以及线粒体膜电位的降低（通过添加JC - 1染料，随后进行FACS分析来确定）证实了外源性和内源性凋亡途径均被激活。最后，作用机制表明不受已知对多种药物耐药的Mel - HO细胞中抗凋亡因子Bcl - 2过表达的影响。综上所述，我们的实验强调了这种新型铼配合物先导结构所固有的独特机会，即在联合治疗中作为一种有效的化疗药物来克服肿瘤中已记录的耐药性。
