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Conditional drug screening shows that mitotic inhibitors induce AKT/PKB-insensitive apoptosis

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Journal of Chemical Biology

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is frequently upregulated in human cancer. Activation of this pathway has been reported to be associated with resistance to various chemotherapeutical agents. We here used a chemical biology/chemical informatic approach to identify apoptotic mechanisms that are insensitive to activation of the PI3K/AKT pathway. The National Cancer Institute (NCI) Mechanistic Set drug library was screened for agents that induce apoptosis in colon carcinoma cells expressing a constitutively active form of AKT1. The cytotoxicity screening data available as self-organized maps at the Developmental Therapeutics Program (DTP) of the NCI was then used to classify the identified compounds according to mechanism of action. The results showed that drugs that interfere with the mitotic process induce apoptosis which is comparatively insensitive to constitutive AKT1 activity. The conditional screening approach described here is expected to be useful for identifying relationships between the state of activation of signaling pathways and sensitivity to anticancer agents.

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Acknowledgements

Dr. Nissim Hay is gratefully acknowledged for the gift of parental and transfected HCT116 myr-AKT cells and Dr. Katja Pokrovskaja is gratefully acknowledged for the gift of the antibody to phosphorylated GSK3β. Grant were received from Cancerfonden, Radiumhemmets forskningsfonder, Vetenskapsrådet and EUFP6 (Chemores, LSHC-CT-2007-037665).

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Authors and Affiliations

  1. Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute and Hospital, Cancer Center Karolinska, R8:00, S-171 76, Stockholm, Sweden

    Maria Berndtsson, Emma Hernlund, Maria C. Shoshan & Stig Linder

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  1. Maria Berndtsson
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  2. Emma Hernlund
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  3. Maria C. Shoshan
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  4. Stig Linder
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Correspondence to Stig Linder.

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Berndtsson, M., Hernlund, E., Shoshan, M.C. et al. Conditional drug screening shows that mitotic inhibitors induce AKT/PKB-insensitive apoptosis. J Chem Biol 2, 81–87 (2009). https://doi.org/10.1007/s12154-009-0017-7

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  • DOI: https://doi.org/10.1007/s12154-009-0017-7

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