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Ferrocene - Cinchona Hybrids with Triazolyl - chalcone Linker Act as Pro-oxidants and Sensitize Human Cancer Cell Lines to Paclitaxel

Abstract

Recently, we demonstrated that ferrocene- containing compounds with cinchona moiety displayed marked anticancer activity. Here we report on the effects of most promising isomers encompassing quinine- (compounds 4 and 5) and quinidine- epimers (compounds 6 and 7) - synthesized by improved methods providing controlled diastereoselectivity - in three different human multidrug resistant (MDR) cancer cell lines and their sensitive counterparts (non-small cell lung carcinoma NCI-H460/R/NCI-H460, colorectal carcinoma DLD1-TxR/DLD1 and glioblastoma U87-TxR/U87). We observed that the presence of MDR phenotype did not diminish the activity of compounds suggesting that ferrocene quinine- and quinidine- epimers are not substrates for P-glycoprotein which was indicated as a major mechanism of MDR in cell lines used. Considering that metal-based anticancer agents could mainly act by increasing ROS production, we investigated the potential of ferrocene - quinidine epimers to generate ROS. We found that 6 and 7 more readily increased ROS production and induced mitochondrial damage in MDR cancer cells. According to cell death analysis, 6 and 7 were more active against MDR cancer cells showing collateral sensitivity. In addition, our data suggest that these compounds could act as inhibitors of autophagy. Importantly, simultaneous treatments of 6 and 7 with paclitaxel (PTX) increased sensitivity of MDR cancer cells to PTX. In conclusion, the ferrocene - quinidine epimers besides being selective towards MDR cancer cells could also possess potential to overcome PTX resistance.

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Publication details

The article was received on 15 Jun 2017, accepted on 13 Jul 2017 and first published on 13 Jul 2017


Article type: Paper
DOI: 10.1039/C7MT00183E
Citation: Metallomics, 2017, Accepted Manuscript
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    Ferrocene - Cinchona Hybrids with Triazolyl - chalcone Linker Act as Pro-oxidants and Sensitize Human Cancer Cell Lines to Paclitaxel

    A. Podolski-Renic, S. Bősze, J. Dinic, L. L. Kocsis, F. Hudecz, A. Csámpai and M. Pesic, Metallomics, 2017, Accepted Manuscript , DOI: 10.1039/C7MT00183E

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