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MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy

Oncogene volume 30, pages 117–126 (2011)Cite this article

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Abstract

Zinc has a crucial role in the biology of p53 in that p53 binds to DNA through a structurally complex domain stabilized by zinc atom. The p53 negative regulator MDM2 protein also carries a C-terminal RING domain that coordinates two zinc atoms, which are responsible for p53 nuclear export and proteasomal degradation. In this clinically translatable study, we explored the critical role of zinc on p53 reactivation by MDM2 inhibitor, MI-219, in colon and breast cancer cells. ZnCl2 enhanced MI-219 activity (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), apoptosis and colony formation), and chelation of zinc not only blocked the activity of MI-219, but also suppressed reactivation of the p53 and its downstream effector molecules p21WAF1 and Bax. N,N,N′N′-tetrakis(−)[2-pyridylmethyl]-ethylenediamine (TPEN), a specific zinc chelator, but not 1,2-bis-(o-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid (Bapta-AM), a calcium chelator, blocked MI-219-induced apoptosis. Nuclear localization is a prerequisite for proper functioning of p53 and our results confirm that TPEN, and not Bapta-AM, could abrogate p53 nuclear localization and it interfered with p53 transcriptional activation. Addition of zinc suppressed the known p53 feedback MDM2 activation, which could be restored by TPEN. Co-immunoprecipitation studies verified that MI-219-mediated MDM2-p53 disruption could be suppressed by TPEN and restored by zinc. As such, single-agent therapies that target MDM2 inhibition, without supplemental zinc, may not be optimal in certain patients owing to the less recognized mild zinc deficiency among the ‘at-risk population’ as in the elderly who are more prone to cancers. Therefore, use of supplemental zinc with MI-219 will benefit the overall efficacy of MIs and this potent combination warrants further investigation.

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Acknowledgements

National Cancer Institute, NIH Grant R01CA109389 (RM Mohammad) and NIH Grant 5R01CA101870 (FH Sarkar) are acknowledged. We sincerely acknowledge the Guido foundation for their support.

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Authors and Affiliations

  1. Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    A S Azmi, Z Wang, S Banerjee & F H Sarkar

  2. Division of Hematology and Oncology, Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    P A Philip, F W J Beck & R M Mohammad

  3. Departments of Internal Medicine and Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA

    S Wang

  4. Ascenta Therapeutics, Inc., Malvern, PA, USA

    S Wang & D Yang

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  1. A S Azmi
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Correspondence to R M Mohammad.

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Competing interests

Dr Ramzi M Mohammad, Dr Fazlul H Sarkar and Dr Shaomeng Wang are funded from the NIH. Dr Shaomeng Wang and Dr Dajun Yang own equity in Ascenta Therapeutics and are consultants for the company and receive compensation for their services. The rest of the authors in this paper have no potential conflict of interest.

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Azmi, A., Philip, P., Beck, F. et al. MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy. Oncogene 30, 117–126 (2011). https://doi.org/10.1038/onc.2010.403

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