Conditional drug screening shows that mitotic inhibitors induce AKT/PKB-insensitive apoptosis |
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Authors: | Maria Berndtsson Emma Hernlund Maria C Shoshan Stig Linder |
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Institution: | (1) Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute and Hospital, Cancer Center Karolinska, R8:00, S-171 76 Stockholm, Sweden |
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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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Keywords: | Chemical biology Apoptosis AKT Microtubuli-interacting agents |
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