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 cel...

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Bibliographic Details
Published in:	Radiation research Vol. 129; no. 3; pp. 345 - 350
Main Authors:	Hallahan, Dennis E., Virudachalam, Subbulakshmi, Schwartz, Jeffrey L., Panje, Nichole, Mustafi, Reba, Weichselbaum, Ralph R.
Format:	Journal Article
Language:	English
Published:	Oak Brook, Il Academic Press, Inc 01-03-1992 Radiation Research Society
Subjects:	1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine 3T3 cells Alkaloids - pharmacology Animal tumors. Experimental tumors B lymphocytes Biological and medical sciences Cell cycle Cell lines Cell Survival - drug effects Cell Survival - radiation effects DNA DNA - drug effects DNA - radiation effects DNA Damage DNA Repair DNA, Single-Stranded - drug effects DNA, Single-Stranded - radiation effects Dose-Response Relationship, Radiation Down-Regulation Elution Experimental tumors, general aspects Gamma cells Humans In Vitro Techniques Ionizing radiation Irradiation Isoquinolines - pharmacology Medical sciences Piperazines - pharmacology Protein Kinase C - antagonists & inhibitors Pyrimidine Nucleosides - pharmacology Radiation-Sensitizing Agents - pharmacology Staurosporine Tumor cell line Tumor Cells, Cultured - drug effects Tumor Cells, Cultured - enzymology Tumor Cells, Cultured - radiation effects Tumors Human Cell culture Nuclear medicine Elution Protein kinase C Carcinoma Enzyme Transferase Instrumentation Malignant tumor Experimental study Result Double strand break Ionizing irradiation Cell line Radiobiology Single strand break Filter DNA Inhibition Damage Tumor cell
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Summary:	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.
ISSN:	0033-7587 1938-5404
DOI:	10.2307/3578035