Mechanism of action of 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone, a SH inhibitory antitumor antibiotic, and its effect on drug-resistant neoplastic cells.
An inhibitor of alkaline phosphodiesterase was isolated from a soil Streptomyces. The agent was identified with 2-crotonyloxymethyl-4,5,6-trihydroxycylohex-2-enone (COTC) by UV, IR, 1H HMR and 13C NMR spectrometry. The mechanism of tumor-inhibitory action of COTC was studied with murine lymphoblastma L5178Y cells. COTC blocked alkaline phosphodiesterase; IC 50 was 60 micrograms/ml by the method employed. The growth of L5178Y cells was inhibited by COTC; IC50 was 4.4 micrograms/ml. DNA biosynthesis was preferentially prevented by COTC over RNA and protein syntheses; IC50 of DNA synthesis was 7 or approximately 25 micrograms/ml. COTC significantly inhibited DNA polymerase alpha even in the presence of dithiothreitol. The mitosis was markedly blocked by COTC; complete inhibition was observed at a drug concentration of 20 microgram/ml. Adriamycin-, aclarubicin- and bleomycin-resisant cell subline showed collateral sensitivity to COTC. COTC and aclarubicin exhibited synergistic activity on aclarubicin-resistant cells, but not on the parental cells. COTC increased uptake of [3H]adriamycin or blocked the drug efflux in the resistance cells, but not in the parental cells. The effects of COTC on macromolecular syntheses, mitosis and membrane functions may be attributed to the interaction with the sulfhydryl group of various enzymes. Although COTC is multifunctional drug, the inhibition of DNA polymerase alpha and a certain mitotic process seems to be related to the lethal action.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D003510:Cyclohexanes / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D004351:Drug Resistance; D007940:Leukemia L5178 / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010726:Phosphodiesterase Inhibitors; D012334:RNA, Neoplasm / Q000096:biosynthesis
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D003512:Cyclohexanones; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D010726:Phosphodiesterase Inhibitors; D012334:RNA, Neoplasm; C011202:2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex- 2-enone; D004317:Doxorubicin; D004259:DNA-Directed DNA Polymerase