Inhibition of protein kinases sensitizes human tumor cells to ionizing radiation.
Protein kinase C (PKC) is activated rapidly and transiently following ionizing radiation exposure and is postulated to activate downstream nuclear signal transducers. Inhibition of this enzyme attenuates radiation-mediated expression of the c-jun and Egr-1/zif-268 genes which are associated with cellular proliferation. To investigate further the role of PKC in the radiation response of human tumor cell lines, two human squamous cell carcinoma cell lines, SQ-20B and JSQ-3, were exposed to graded doses of X rays in the presence of staurosporine, sangivamycin, or H7, all PKC inhibitors. The protein kinase inhibitors staurosporine and sangivamycin produced dose-dependent cytotoxicity in cells of the SQ-20B and JSQ-3 cell lines while H7 did not. Nontoxic concentrations of sangivamycin (10 nM) and staurosporine (1 nM), added to cell cultures from 1 to 7 h before X irradiation, enhanced cell killing by radiation in both cell lines. Maximal sensitization of killing occurred when inhibitors were added 1 h prior to irradiation. The enhanced radiation-induced cell killing was not due to any measurable alteration in the induction or rejoining of DNA single- or double-strand breaks as determined by alkaline and neutral filter elution assays. These data suggest that protein kinase activity is important for cell survival following radiation exposure, although the specific role of PKC in radiation responses is unknown.
Hallahan
D E
DE
Department of Radiation and Cellular Oncology, University of Chicago, Illinois 60637.
Virudachalam
S
S
Schwartz
J L
JL
Panje
N
N
Mustafi
R
R
Weichselbaum
R R
RR
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011741:Pyrimidine Nucleosides / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D019311:Staurosporine; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects*
D000470:Alkaloids; D004277:DNA, Single-Stranded; D007546:Isoquinolines; D010879:Piperazines; D011741:Pyrimidine Nucleosides; D011838:Radiation-Sensitizing Agents; C005699:sangivamycin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D004247:DNA; D011493:Protein Kinase C; D019311:Staurosporine