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 in vitro anti-proliferative properties of a phenanthridine-containing Re^I(CO)₃ complex (compound 1, 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 p-glycoproteins as was confirmed by measuring the amount of hypodiploid DNA via 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.

中文翻译：

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有机金属Re ^I-菲啶复合物的抗性分析和基因表达分析揭示了两条细胞凋亡途径的平行激活

肿瘤对多种抗癌药的新兴耐药性是各种癌症的化学治疗中的主要关注点。显然，这引起了对具有新作用方式的新型疗法的需求。本文中，我们报道了含有菲啶的Re ^I（CO）₃复合物（化合物1，也缩写为LR-166）的体外抗增殖特性，并确定了对其作用方式的主要贡献。复杂的诱导凋亡在低微摩尔浓度甚至在耐药伯基特样淋巴瘤（BJAB）和白血病（NALM-6）细胞系的已知的过表达p -glycoproteins如通过测量亚二倍体DNA的量确认通过FACS扫描分析。重要的是，对多种修饰的细胞系（白血病：NALM-6，淋巴瘤：BJAB，黑素瘤：MelHO）进行基因表达分析和毒性研究，并降低了线粒体膜电位（通过添加JC-1染料确定），通过FACS分析）证实了外在和内在凋亡途径均被激活。最后，显示出其作用机理不受已知对多种药物具有抗性的Mel-HO细胞中抗凋亡因子Bcl-2的过表达的影响。综上所述，我们的实验强调了Re复合物这种新型先导结构固有的独特机会，可以在联合疗法中作为有效的化学治疗剂来克服已证明的对肿瘤的耐药性。