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Cytotoxic behavior of binuclear silver N-heterocyclic carbenes in HCT 116 cells and influence of substitution on cytotoxicity

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Abstract

Ag (I)-N-heterocyclic carbene (Ag–NHC) complexes (S1–S6) were synthesized from di-cationic ionic liquids (DCILs-1–6) and characterized by NMR, FT-IR, and EI-MS studies, and evaluated for cytotoxicity against human colorectal carcinoma cell line (HCT-116) using methylthiazolyldiphenyl-tetrazolium bromide assay. The DCILs displayed good patterns of cytotoxicity which was improved greatly upon metallation and were found to be in a direct correlation with the increase in the alkyl chain that correlates with lipophilicity. Amongst the Ag–NHCs studied, S1, S5, and S6 have shown 85.95, 99.01 and 99.70% growth inhibition at the concentrations of 120, 120 and 60 µM, respectively. In order to depict the putative mechanism adopted by S6, HCT-116 cells were treated with S6 and stained using acridine orange/ethidium bromide (AO/EtBr), and the results displayed a significant induction of apoptosis in HCT-116 cells as evident from the green-orange fluorescence. Furthermore, DAPI staining confirmed that the S6-treated HCT-116 cells underwent chromatin condensation and DNA fragmentation. Since mitochondria play a prominent role in apoptosis, we further examined the mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) formation. Interestingly, the S6-treated HCT-116 cells demonstrated a higher ROS and depolarization of MMP, which suggests that S6 can induce mitochondria-mediated intrinsic apoptosis in cancer cells. Besides these consequences, HCT-116 cells also exhibited a lower level of oxidant defensive protein catalase. Taken altogether, the current study suggests that Ag–NHCs can reduce anti-oxidative protein catalase following an increase in ROS level, thereby triggering apoptosis in cancer cells.

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Acknowledgements

We gratefully acknowledge SIF DST-VIT-FIST, VIT University, Vellore, for providing NMR data as well as other required facilities. The authors are also grateful to all members of the “Smart Material Laboratory for Biosensing and Catalysis ” for their continuous support. Dr. Asit Ranjan Ghosh is grateful to the VIT University for promoting research by financial support through RGEMS-2016. V.D. would like to acknowledge CSIR for a Senior Research Fellowship.

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Authors and Affiliations

  1. Department of Chemistry, School of Advanced Sciences, VIT University, Vellore, 632014, India

    Sainath B. Aher, K. Thenmozhi & Pundlik R. Bhagat

  2. Department of Chemistry, Amlokchand Mahavidyalaya, Yavatmal, Sant Gadge Baba Amravati University, Amravati, 444602, India

    Prashant N. Muskawar

  3. Center for Infectious Diseases and Control, VIT University, Vellore, 632014, India

    Vinay Dubey & Asit Ranjan Ghosh

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  1. Sainath B. Aher
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  2. Vinay Dubey
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Correspondence to Pundlik R. Bhagat.

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Aher, S.B., Dubey, V., Muskawar, P.N. et al. Cytotoxic behavior of binuclear silver N-heterocyclic carbenes in HCT 116 cells and influence of substitution on cytotoxicity. Res Chem Intermed 43, 4851–4862 (2017). https://doi.org/10.1007/s11164-017-2916-5

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