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Dual Inhibition of PI3K/Akt Signaling and the DNA Damage Checkpoint in p53-Deficient Cells with Strong Survival Signaling: Implications for Cancer Therapy
Andrzej Skladanowski, Przemyslaw Bozko, Michal Sabisz and Annette K. Larsen
volume 6 | issue 18
15 September 2007Pages: 2268 - 2275
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Natural (intrinsic) resistance of many tumor types to DNA damaging agents is closely associated with their capacity to undergo robust cell cycle arrest in G2/M. G2 arrest is regulated by the DNA damage checkpoint and by survival signaling, with a potential role of PI3K/Akt in checkpoint function. In this work, we wanted to clarify if inhibition of multiple checkpoint/survival pathways may confer better efficacy in the potentiation of genotoxic agents compared to inhibition of either pathway alone. We compared the influence of UCN-01, which affects both the DNA damage checkpoint and PI3K/Akt-mediated survival signaling, with the PI3K inhibitors wortmannin and LY294002 in p53-deficient M1 acute myeloid leukemia cells treated with the DNA damaging agent cisplatin. Our results show that direct inhibition of PI3K/Akt in G2-arrested cells by wortmannin or LY294002 strongly enhanced the cytotoxicity of cisplatin without influencing the G2 checkpoint. Unexpectedly, dual inhibition of both survival and checkpoint signaling by UCN-01, also increased the cytotoxicity of cisplatin, but to a lesser degree than wortmannin or LY294002. The differences in cytotoxicity were accompanied by differences in cell death pathways: direct inhibition of PI3K/Akt was accompanied by rapid apoptotic cell death during G2, whereas cells underwent mitotic transit and cell division followed by cell death during G1 when both checkpoint and survival signaling were inhibited. Our results elucidate a novel function for PI3K/Akt as a survival factor during DNA damage-induced G2 arrest and could have important pharmacological consequences for the application of response modulators in p53-deficient tumors with strong survival signaling.
Authors
Andrzej Skladanowski
Gdansk University of Technology
Przemyslaw Bozko
Gdansk University of Technology; Gdansk, Poland
Michal Sabisz
Gdansk University of Technology; Gdansk, Poland
Annette K. Larsen
Université Pierre et Marie Curie; Paris, France