Differential p53-dependent mechanism of radiosensitization in vitro and invivo by the protein kinase C-specific inhibitor PKC412

The cellular response to ionizing radiation is governed by the DNA-damage r ecognition process but is also modulated by cytoplasmic signal transduction cascades that are part of the cellular stress response. Growth-promoting p rotein kinase C activity antagonizes irradiation-induced cell death, and, t herefore, protein kinase C inhibitors might be patent radiosensitizers. The antiproliferative and radiosensitizing effect of the novel N-benzoylated s taurosporine analogue PKC412 was tested ill vitro against genetically defin ed p53-wild type (+/+) and p53-deficient (-/-) murine fibrosarcoma cells an d in vivo against radioresistant p53-/- murine fibrosarcoma and human colon adenocarcinoma tumor xenograft (SW480, p53-mutated), PKC412 sensitized bot h p53+/+ and p53-/- tumor cells in vitro and in vivo for treatment with ion izing radiation but with a different mechanism of radiosensitization depend ing on the p53 status. In p53+/+, cells combined treatment with PKC412 and ionizing radiation drastically induced apoptotic cell death, whereas no apo ptosis induction could be observed in p53-deficient cells in vitro and in h istological tumor sections, Combined treatment resulted in an increased G(2 ) cell cycle distribution in p53-/- cells at PKC412 concentrations that did not alter cell cycle distribution when applied alone. In vivo, a minimal t reatment regimen during 4 consecutive days of PKC412 (4 x 100 md/kg) in com bination with ionizing radiation (4 x 3 Gy) exerted a substantial tumor gro wth delay for both p53-disfunctional tumor xenografts and showed that the c linically relevant protein kinase C inhibitor PKC412 Is a promising new rad iosensitizer with a potentially broad therapeutic window.