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Copper-imidazo[1,2-a]pyridines induce intrinsic apoptosis and modulate the expression of mutated p53, haem-oxygenase-1 and apoptotic inhibitory proteins in HT-29 colorectal cancer cells

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Abstract

Metastatic colorectal cancer responds poorly to treatment and is a leading cause of cancer related deaths. Worldwide, chemotherapy of metastatic colorectal cancer remains plagued by poor efficacy, development of resistance and serious adverse effects. Copper-imidazo[1,2-a]pyridines were previously shown by our group to be selectively active against several cancer cell lines, with three complexes, JD46(27), JD47(29), and JD88(21), showing IC50 values between 0.8 and 1.8 μM against HT-29 cells. Here, we report that treatment with the copper complexes resulted in fragmented nuclei suggestive of apoptotic cell death, which was confirmed by increased annexin V binding and caspase-3/7 activity. The copper complexes caused a loss of mitochondrial membrane potential and increased caspase-9 activity. The absence of caspase-8 activity indicated activation of the intrinsic pathway. Proteomic analysis revealed that copper-imidazo[1,2-a]pyridines decreased the expression of phosphorylated forms of p53 [phospho-p53(S15), phospho-p53(S46) and phospho-p53(S392)]. The expression of inhibitor of apoptosis proteins, XIAP, cIAP1, livin, and the antiapoptotic proteins, Bcl-2 and Bcl-x, was decreased. HO/HMOX/HSP32, expression was notably increased, which suggested the accumulation of reactive oxygen species. Increased expression of TRAIL-R2/DR5 death receptor indicated the possible dual activation of both the extrinsic and intrinsic apoptotic pathways; however, caspase-8 activation could not be demonstrated. In conclusion, the copper-imidazo[1,2-a]pyridines were effective inducers of apoptotic cell death at low micromolar concentrations and changed the expression levels of proteins important for cell survival and cell death. These copper complexes may be useful tools to better understand the complexity of signalling networks in cancer cell death in response to cell stress.

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Acknowledgements

This work was supported by the Blue Skies Initiative of the National Research Foundation, Pretoria (South Africa), the Southern African Biochemistry and Informatics for Natural Products Network (SABINA) and the University of the Witwatersrand (Science Faculty Research and Health Sciences Faculty Research Councils) as well as the McGill bequest to the Pharmacology Division.

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  1. Division of Pharmacology, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa

    Leonie Harmse, Nadia Gangat & Carla Martins-Furness

  2. Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, Johannesburg, 2050, South Africa

    Jean Dam & Charles B. de Koning

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  1. Leonie Harmse
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  2. Nadia Gangat
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  3. Carla Martins-Furness
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  4. Jean Dam
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  5. Charles B. de Koning
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Correspondence to Leonie Harmse.

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Harmse, L., Gangat, N., Martins-Furness, C. et al. Copper-imidazo[1,2-a]pyridines induce intrinsic apoptosis and modulate the expression of mutated p53, haem-oxygenase-1 and apoptotic inhibitory proteins in HT-29 colorectal cancer cells. Apoptosis 24, 623–643 (2019). https://doi.org/10.1007/s10495-019-01547-7

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