Abrogation of G2 checkpoint specifically sensitize p53 defective cells to cancer chemotherapeutic agents.
BACKGROUND
Chkl is a checkpoint gene that is activated after DNA damage. It phosphorylates and inactivates Cdc25C at the late G2 phase. The inactivation of Cdc25C and consequently, the inactivation of Cdc2, are required for the G2 arrest induced by DNA damage.


METHODS
We treated 184B5 cell line and its E6 transformed cell lines with adriamycin in the presence of staurosporine or UCNO1 and examined G2 arrest and cell death.


RESULTS
We found that adriamycin induced a p53 and p21 response as well as a G1 arrest in 184B5 cells, but not in its E6 transformed cells. Staurosporine or UCNO1 abrogated the G2 arrest induced by adriamycin in both cell lines. In addition, staurosporine or UCNO1 specifically sensitized p53 incompetent cells to adriamycin.


CONCLUSIONS
G2/M checkpoint abrogators can potentially enhance the cytotoxic effect of conventional chemotherapeutic reagents specifically to tumor cells.
Luo
Y
Y
Department 47S AP9A, Cancer Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
Rockow-Magnone
S K
SK
Joseph
M K
MK
Bradner
J
J
Butler
C C
CC
Tahir
S K
SK
Han
E K
EK
Ng
S C
SC
Severin
J M
JM
Gubbins
E J
EJ
Reilly
R M
RM
Rueter
A
A
Simmer
R L
RL
Holzman
T F
TF
Giranda
V L
VL
D000470:Alkaloids / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002461:Cell Line, Transformed; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016195:G2 Phase; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000470:Alkaloids; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; C054852:7-hydroxystaurosporine; D004317:Doxorubicin; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D019311:Staurosporine