Decreasing the apoptotic threshold of tumor cells through protein kinase C inhibition and sphingomyelinase activation increases tumor killing by ionizing radiation.
Approximately 30% of cancer deaths result from the failure to control local and regional tumors. The goal of radiotherapy is to maximize local and regional tumor cell killing while minimizing normal tissue destruction. Attempts to enhance radiation-mediated tumor cell killing using halogenated pyrimidines, antimetabolites, and other DNA-damaging agents or sensitizers of hypoxic tumor cells have met with only modest clinical success. In an unique strategy to modify tumor radiosensitivity, we used an inhibitor of the protein kinase C group A and B isoforms, chelerythrine chloride (chelerythrine), to enhance the killing effects of ionizing radiation (IR). Protein kinase C activity plays a central role in cellular proliferation, differentiation, and apoptosis. Chelerythrine increases sphingomyelinase activity and enhances IR-mediated cell killing through induction of apoptotic tumor cell death in a radioresistant tumor model both in vitro and in vivo. Although previous reports have suggested that IR-mediated apoptosis correlates with tumor volume reduction, we demonstrate for the first time that lowering the apoptotic threshold increases tumor cell killing in vivo.
Chmura
S J
SJ
Department of Pathology, University of Chicago and the Pritzker School of Medicine, Illinois 60637, USA.
Mauceri
H J
HJ
Advani
S
S
Heimann
R
R
Beckett
M A
MA
Nodzenski
E
E
Quintans
J
J
Kufe
D W
DW
Weichselbaum
R R
RR
D000470:Alkaloids; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053119:Benzophenanthridines; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy*; D002518:Ceramides / Q000494:pharmacology; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D006259:Craniocerebral Trauma / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy*; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D014183:Transplantation, Heterologous
D000470:Alkaloids; D053119:Benzophenanthridines; D002518:Ceramides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009363:Neoplasm Proteins; D010617:Phenanthridines; D011838:Radiation-Sensitizing Agents; C016299:chelerythrine; D011493:Protein Kinase C; D013108:Sphingomyelin Phosphodiesterase; D010450:Endopeptidases