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Issue 1, 2018
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Resistance-breaking profiling and gene expression analysis on an organometallic ReI–phenanthridine complex reveal parallel activation of two apoptotic pathways

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Abstract

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 ReI(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.

Graphical abstract: Resistance-breaking profiling and gene expression analysis on an organometallic ReI–phenanthridine complex reveal parallel activation of two apoptotic pathways

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Publication details

The article was received on 27 Oct 2017, accepted on 01 Dec 2017 and first published on 20 Dec 2017


Article type: Research Article
DOI: 10.1039/C7MD00545H
Citation: Med. Chem. Commun., 2018,9, 173-180
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    Resistance-breaking profiling and gene expression analysis on an organometallic ReI–phenanthridine complex reveal parallel activation of two apoptotic pathways

    M. König, D. Siegmund, L. J. Raszeja, A. Prokop and N. Metzler-Nolte, Med. Chem. Commun., 2018, 9, 173
    DOI: 10.1039/C7MD00545H

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