Dual inhibition of PI3K/Akt signaling and the DNA damage checkpoint in p53-deficient cells with strong survival signaling: implications for cancer therapy.
Natural (intrinsic) resistance of many tumor types to DNA damaging agents is closely associated with their capacity to undergo robust cell cycle arrest in G(2)/M. G(2) 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 G(2)-arrested cells by wortmannin or LY294002 strongly enhanced the cytotoxicity of cisplatin without influencing the G(2) 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 G(2), whereas cells underwent mitotic transit and cell division followed by cell death during G(1) 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 G(2) arrest and could have important pharmacological consequences for the application of response modulators in p53-deficient tumors with strong survival signaling.
Skladanowski
Andrzej
A
Group of Cancer Biology and Therapeutics, INSERM U673 and Université Pierre et Marie Curie, Hôpital Saint-Antoine, Paris, France.
Bozko
Przemyslaw
P
Sabisz
Michal
M
Larsen
Annette K
AK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016159:Tumor Suppressor Protein p53