Abstract
Leucinostatin, an antimicrobial and antitumor antibiotic, was found to be cytotoxic to the murine leukemic cell line, L 1210. A complete inhibition of cell growth was achieved with 0.5 μg of the drug per ml. Leucinostatin showed membrane damage against L 1210 cells as well as mouse erythrocytes. L 1210 cells were partially protected from membrane damage by the addition of glucose to the medium. In contrast, no protective effect of glucose was observed with drug-induced hemolysis. The possible involvement of membrane lipid in the mechanism of action of leucinostatin is suggested by its action on liposomes. Liposomes prepared with lecithin, cholesterol, and an amphiphatic molecule, either dicetyl phosphate or stearylamine, were sensitive to leucinostatin and response to the drug was enhanced as the cholesterol level of liposomes was decreased. Changes in the net charge of the membrane did not show significant effects on leucinostatin action. In the presence of the antibiotic, on the other hand, protein synthesis in cells was markedly inhibited under conditions where the uptake of amino acids into an acid-soluble pool was not affected. However, leucinostatin did not exhibit any inhibitory effect on protein synthesis in a cell-free system from L 1210 cells. It is suggested that the inhibition of protein synthesis results from the initial interaction of the drug with membrane phospholipid.
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Selected References
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- Arai T., Mikami Y., Fukushima K., Utsumi T., Yazawa K. A new antibiotic, leucinostatin, derived from Penicillium lilacinum. J Antibiot (Tokyo) 1973 Mar;26(3):157–161. doi: 10.7164/antibiotics.26.157. [DOI] [PubMed] [Google Scholar]
- BARTLETT G. R. Phosphorus assay in column chromatography. J Biol Chem. 1959 Mar;234(3):466–468. [PubMed] [Google Scholar]
- Dunham P. B., Goldstein I. M., Weissmann G. Potassium and amino acid transport in human leukocytes exposed to phagocytic stimuli. J Cell Biol. 1974 Oct;63(1):215–226. doi: 10.1083/jcb.63.1.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Godefroi E. F., Heeres J., Van Cutsem J., Janssen P. A. The preparation and antimycotic properties of derivatives of 1-phenethylimidazole. J Med Chem. 1969 Sep;12(5):784–791. doi: 10.1021/jm00305a014. [DOI] [PubMed] [Google Scholar]
- HsuChen C. C., Feingold D. S. The mechanism of polymyxin B action and selectivity toward biologic membranes. Biochemistry. 1973 May 22;12(11):2105–2111. doi: 10.1021/bi00735a014. [DOI] [PubMed] [Google Scholar]
- Inoue K., Kitagawa T. Effect of exogenous lysolecithin on liposomal membranes. Its relation to membrane fluidity. Biochim Biophys Acta. 1974 Sep 23;363(3):361–372. doi: 10.1016/0005-2736(74)90075-3. [DOI] [PubMed] [Google Scholar]
- Inoue K. Permeability properties of liposomes prepared from dipalmitoyllecithin, dimyristoyllecithin, egg lecithin, rat liver lecithin and beef brain sphingomyelin. Biochim Biophys Acta. 1974 Mar 29;339(3):390–402. doi: 10.1016/0005-2736(74)90166-7. [DOI] [PubMed] [Google Scholar]
- Kinsky S. C., Haxby J. A., Zopf D. A., Alving C. R., Kinsky C. B. Complement-dependent damage to liposomes prepared from pure lipids and Forssman hapten. Biochemistry. 1969 Oct;8(10):4149–4158. doi: 10.1021/bi00838a036. [DOI] [PubMed] [Google Scholar]
- Kuo S. C., Lampen J. O. The action of antibiotics on enzyme secretion in yeasts: studies with cytochalasin A. Ann N Y Acad Sci. 1974 May 10;235(0):137–148. doi: 10.1111/j.1749-6632.1974.tb43263.x. [DOI] [PubMed] [Google Scholar]
- Ladbrooke B. D., Williams R. M., Chapman D. Studies on lecithin-cholesterol-water interactions by differential scanning calorimetry and X-ray diffraction. Biochim Biophys Acta. 1968 Apr 29;150(3):333–340. doi: 10.1016/0005-2736(68)90132-6. [DOI] [PubMed] [Google Scholar]
- Plagemann P. G., Roth M. F. Permeation as the rate-limiting step in the phosphorylation of uridine and choline and their incorporation into macromolecules by Novikoff hepatoma cells. Competitive inhibition by phenethyl alcohol, persantin, and adenosine. Biochemistry. 1969 Dec;8(12):4782–4789. doi: 10.1021/bi00840a020. [DOI] [PubMed] [Google Scholar]
- Plagemann P. G., Ward G. A., Mahy B. W., Korbecki M. Relationship between uridine kinase activity and rate of incorporation of uridine into acid-soluble pool and into RNA during growth cycle of rat hepatoma cells. J Cell Physiol. 1969 Jun;73(3):233–249. doi: 10.1002/jcp.1040730308. [DOI] [PubMed] [Google Scholar]
- Plempel M., Bartmann K., Büchel K. H., Regel E. Experimentelle Befunde über ein neues, oral wirksames Antimykotikum mit breiten Wirkungsspektrum. Dtsch Med Wochenschr. 1969 Jun 27;94(26):1356–passim. doi: 10.1055/s-0028-1111223. [DOI] [PubMed] [Google Scholar]