p53-dependent G(1) arrest in 1st or 2nd cell cycle may protect human cancer cells from cell death after treatment with ionizing radiation and Chk1 inhibitors.
OBJECTIVE
This study was performed to explore the strategy of combining Chk1 inhibitors with ionizing radiation (IR) to selectively target p53-deficient cancer cells.


METHODS
Survival and cell cycle progression were measured in response to IR and the Chk1 inhibitors, UCN-01 and CEP-3891, in colon carcinoma HCT116 p53+/+ and p53-/- cells, and in osteosarcoma U2OS-VP16 cells with conditional expression of dominant-negative p53 (p53DD).


RESULTS
Clonogenic survival was selectively reduced in HCT116 p53-/- compared to p53+/+ cells after treatment with UCN-01 and IR, and HCT116 p53+/+ cells also displayed strong p53-dependent G(1) arrest in the 1st cell cycle after IR. In contrast, clonogenic survival was affected similarly in U2OS-VP16 cells with and without expression of p53DD. However, death of U2OS-VP16 cells was p53 dependent as assessed by cell viability assay at 72 h, and this was associated with p53-dependent G(1) arrest in the 2nd cell cycle after treatment. Notably, HCT116 cells were overall more resistant than U2OS cells to cytotoxic effects of Chk1 inhibitors.


CONCLUSIONS
Our results suggest that p53-dependent G(1) arrest in both 1st and 2nd cell cycles may protect human cancer cells from cell death after treatment with IR and Chk1 inhibitors. However, a challenge for future clinical use will be that different cancers display different intrinsic sensitivity to such inhibitors.
Petersen
L
L
Department of Radiation Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Hasvold
G
G
Lukas
J
J
Bartek
J
J
Syljuåsen
R G
RG
D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016158:Genes, p53 / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D009423:Nervous System Neoplasms / Q000235:genetics; D011494:Protein Kinases; D011839:Radiation, Ionizing; D019311:Staurosporine / Q000031:analogs & derivatives; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D016159:Tumor Suppressor Protein p53; C054852:7-hydroxystaurosporine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D019311:Staurosporine