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Effects of Gliotoxin and Other Sulfur-Containing Compounds on Tumor Cells in vitro^1,2,

With Observations on the Mechanism of Action of Gliotoxin

From the Department of Pathology, The New York Hospital, Cornell Medical Center New York 21, New York

Abstract

Gliotoxin in concentrations of 1 µg/ml or more regularly inhibited the subsequent growth of mouse lymphosarcoma cells after contact with them in vitro during a period of 1 hour at 37 C. Desthiogliotoxin, by contrast, had no effect on the tumor cells in concentrations of 800 µg/ml in comparable tests. All of five synthetic compounds having cyclic disulfide components like that of gliotoxin inhibited the tumor cells in concentrations ranging from 5 to 50 µg/ml. In similar tests these compounds and gliotoxin likewise inhibited the growth of mammary carcinoma cells of C3H mice, though in all instances concentrations several times greater than those inhibitory for the lymphosarcoma cells were required.

The inhibitory effect of gliotoxin was abolished when it was mixed before being brought into contact with tumor cells with high concentrations of cysteine, glutathione, or monothioglycerol at pH 7.4. When gliotoxin was allowed to react with the tumor cells first, however, the sulfhydryl compounds applied subsequently in high concentrations did not alter its inhibitory effect, and this was not prevented when the tumor cells were treated with the sulfhydryl compounds beforehand.

Gliotoxin was found to be equally effective against tumor cells under aerobic and partially anaerobic conditions in vitro. BAL, however, was considerably less effective against tumor cells when air was excluded from the mixture.

The findings as a whole indicate that the cyclic disulfide linkage is essential for the effect of gliotoxin on tumor cells in vitro. Their implications are briefly considered.

Footnotes

¹ Preliminary Note in Federation Proc. 8: 407, 1949.

² Aided by a grant from the United States Public Health Service.