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9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

Oncogene volume 28, pages 1151–1161 (2009)Cite this article

Abstract

Acquisition of a transformed phenotype involves deregulation of several signal transduction pathways contributing to unconstrained cell growth. Understanding the interplay of different cancer-related signaling pathways is important for development of efficacious multitargeted anticancer drugs. The small molecule 9-aminoacridine (9AA) and its derivative, the antimalaria drug quinacrine, have selective toxicity for tumor cells and can simultaneously suppress nuclear factor-κB (NF-κB) and activate p53 signaling. To investigate the mechanism underlying these drug activities, we used a combination of two-dimensional protein separation by gel electrophoresis and mass spectrometry to identify proteins whose expression is altered in tumor cells by 9AA treatment. We found that 9AA treatment results in selective downregulation of a specific catalytic subunit of the phosphoinositide 3-kinase (PI3K) family, p110γ. Further exploration of this observation demonstrated that the mechanism of action of 9AA involves inhibition of the prosurvival AKT/mammalian target of rapamycin (mTOR) pathway that lies downstream of PI3K. p110γ translation appears to be regulated by mTOR and feeds back to further modulate mTOR and AKT, thereby impacting the p53 and NF-κB pathways as well. These results reveal functional interplay among the PI3K/AKT/mTOR, p53 and NF-κB pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by a single small molecule such as 9AA could result in efficacious and selective killing of transformed cells.

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Authors and Affiliations

  1. Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA

    C Guo

  2. Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    C Guo

  3. Cleveland Biolabs Inc., Buffalo, NY, USA

    A V Gasparian, D A Bosykh, A V Gudkov & K V Gurova

  4. National Institutes of Health, Bethesda, MD, USA

    Z Zhuang

  5. Department of Biology, Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH, USA

    A A Komar

  6. Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA

    A V Gudkov & K V Gurova

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  1. C Guo
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  2. A V Gasparian
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  4. D A Bosykh
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  6. A V Gudkov
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  7. K V Gurova
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Correspondence to A V Gudkov or K V Gurova.

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Guo, C., Gasparian, A., Zhuang, Z. et al. 9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways. Oncogene 28, 1151–1161 (2009). https://doi.org/10.1038/onc.2008.460

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  • DOI: https://doi.org/10.1038/onc.2008.460

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