Antitumor effects of butyrolactone I, a selective cdc2 kinase inhibitor, on human lung cancer cell lines.
Butyrolactone I, which is a naturally occurring specific inhibitor of the cdc2 kinase family, showed antitumor effects on several non-small- and small-cell-lung cancer cell lines with IC50 values the order of 50 micrograms/ml on the former. No cross-resistance of several drug-resistant cell lines, including those with the multidrug-resistant phenotype and five cisplatin-resistant cell lines to butyrolactone I was observed. The cdc2 kinase activity of PC-14 cells was inhibited by treatment with 20 micrograms/ml butyrolactone I, a concentration comparable to the IC50 value, for 2 hours. Longer exposure to butyrolactone I (> 24 hours) reduced the cdc2 kinase protein level. Butyrolactone I arrested the cells at the G2/M phase in a concentration dependent manner. These results suggest that butyrolactone I actually acts on cdc2 kinase, rather than other cdk kinases, in PC-14 cells. Inhibition of DNA synthesis, determined by measuring thymidine uptake, occurred earlier (2 hours) after initiating exposure than the decrease in the cdc2 protein level and was concentration dependent, suggesting that butyrolactone I inhibited DN4 synthesis. Cell permeabilization by digitonin enhanced DN4 synthesis inhibition by butyrolactone I, suggesting that the permeability of the membrane to this agent was the limiting factor for its growth inhibitory effect. Many anticancer agents, such as alkylating agents and cisplatin, cause cells to accumulate at the G2/M phase of the cell cycle. We investigated whether butyrolactone I had any modulatory effect on the antitumor effects of several anticancer drugs in vitro. Butyrolactone I showed no modulatory effects on vindesine, paclitaxel, or etoposide, but exposure of PC-9 and PC-14 cells to butyrolactone I together with or prior to treatment with cisplatin reduced the cytotoxicity of the latter. Thin-layer chromatographic analysis revealed that butyrolactone I bound to cisplatin, which was a possible cause of the reduced cisplatin cytotoxicity in the presence of bytyrolactone I.
Nishio
K
K
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Ishida
T
T
Arioka
H
H
Kurokawa
H
H
Fukuoka
K
K
Nomoto
T
T
Fukumoto
H
H
Yokote
H
H
Saijo
N
N
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000201:enzymology* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C082868:butyrolactone I; D016203:CDC2 Protein Kinase; D015107:4-Butyrolactone; D002945:Cisplatin