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The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

Oncogene volume 34, pages 3336–3348 (2015)Cite this article

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Abstract

Topoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes.

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Acknowledgements

We are most grateful to Fred Bunz, Alan D’Andrea, Eva Petermann, Panagiotis Kotsantis and Jiri Lukas for the gift of cell lines, and Philip Byrd, Arnold Levine and David Lane for antibodies. We would especially like to thank Cyrus Vaziri for providing cell lines and a recombinant adenovirus expressing Cyclin E, Rebbeca Jones for helping us with PFGE and Malcolm Taylor for helpful discussions. Last, we would also thank the University of Birmingham (AT—PhD studentship), MRC (GSS, RJG—Project grant: G0900088), the Cancer Research UK (GSS—Senior Fellowship: C17183/A13030), the Leukaemia Lymphoma Research (TS, GSS—Programme grant: 11045), the Lister Institute (GSS, AZ—Research Prize) and the Yorkshire Cancer Research (KP) for funding this study.

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Authors and Affiliations

  1. IBR West Extension, School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK

    A Thomas, T Perry, S Berhane, C Oldreive, A Zlatanou, L R Williams, V J Weston, T Stankovic, P Kearns, R J Grand & G S Stewart

  2. Institute of Cancer Therapeutics, School of Life Sciences, University of Bradford, West Yorkshire, UK

    K Pors

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  1. A Thomas
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Correspondence to K Pors, R J Grand or G S Stewart.

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Thomas, A., Perry, T., Berhane, S. et al. The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53. Oncogene 34, 3336–3348 (2015). https://doi.org/10.1038/onc.2014.266

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  • DOI: https://doi.org/10.1038/onc.2014.266

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