Antitumor activity of protein kinase C inhibitors and cisplatin in human head and neck squamous cell carcinoma lines.
Protein kinase C (PKC) plays a pivotal role in signal transduction involved in the control of cell proliferation, differentiation and apoptosis. Interference with such signaling pathways may result in altered tumor cell response to antineoplastic drugs. We investigated the effects of two selective PKC inhibitors as single agents and in combination with cisplatin in cell lines derived from squamous cell carcinomas of the head and neck (SCCHN). Safingol (Saf) is directed against the regulatory domain, whereas chelerythrine (Che) interacts with the catalytic domain of PKC. In six SCCHN cell lines (UM-SCC 11B, 14A, 14C and 22B, 8029NA, and a 5-fold cisplatin-resistant subline 8029DDP). PKC activities ranged between 1 and 158 IU/1 x 10(7) cells, and they were inversely proportional to the amount of cellular epidermal growth factor receptor. Using the colorimetric MTT assay, PKC inhibitors Saf and Che showed comparable dose-dependent growth inhibition. The 50% inhibitory concentrations (IC50) were between 3.8-8.6 microM for Saf and 8.5-13.6 microM for Che with no relationship to PKC activity or cisplatin sensitivity of the respective cell lines. Combinations of cisplatin (IC50 = 0.4-5.8 microg/ml) and either PKC inhibitor (5 microM Saf, 10 microM Che) led to a significant decrease of cisplatin IC50 values in most cell lines. However, comparison with theoretical additive dose-response curves showed additive rather than synergistic effects for both PKC inhibitors.
Hoffmann
Thomas K
TK
Department of Otorhinolaryngology/Head & Neck Surgery, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
Leenen
Katrin
K
Hafner
Dieter
D
Balz
Vera
V
Gerharz
Claus D
CD
Grund
Adrian
A
Balló
Hilmar
H
Hauser
Ulrich
U
Bier
Henning
H
D000470:Alkaloids; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053119:Benzophenanthridines; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D010617:Phenanthridines / Q000008:administration & dosage; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D010617:Phenanthridines; C016299:chelerythrine; D066246:ErbB Receptors; D011493:Protein Kinase C; D013110:Sphingosine; C005682:safingol; D002945:Cisplatin