Inhibition of glutathione synthesis augments lysis of murine tumor cells by sulfhydryl-reactive antineoplastics.
Inhibition of glutathione synthesis augments lysis of murine tumor cells by sulfhydryl-reactive antineoplastics.
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谷胱甘肽合成的抑制增强了巯基反应性抗肿瘤药物对小鼠肿瘤细胞的溶解。
DOI：
10.1172/jci110766
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发表时间：
1983
期刊：
影响因子：
--
通讯作者：
Cohn,ZA
中科院分区：
文献类型：
--
作者：
Arrick,BA;Nathan,CF;Cohn,ZA
GSH plays an important role in cellular defense against a wide variety of toxic electrophiles via the formation of thioether conjugates. We studied the role of GSH in murine tumor cell defense against a novel class of sulfhydryl-reactive antineoplastics, the sesquiterpene lactones (SL). Incubation of P815 mastocytoma cells with any of the four SL tested (vernolepin, helenalin, elephantopin, and eriofertopin) for 1 h resulted in 70-97% depletion of GSH. The importance of GSH resynthesis upon exposure of tumor cells to SL was evaluated with the use of buthionine sulfoximine (BSO), a selective, nontoxic inhibitor of gamma-glutamylcysteine synthetase. Inhibition of GSH synthesis with 0.2 mM BSO markedly enhanced SL-mediated cytolysis of four murine tumor cell lines. A 6- to 34-fold reduction in the amount of SL causing 50% lysis was obtained with BSO. Addition of BSO to P815cells either during or immediately after a 1-h pulse with 10 micrograms/ml of vernolepin increased cytolysis from less than 3% to 78-82%. However, a 1.5-h delay in the addition of BSO to such cells, which allowed for substantial resynthesis of GSH, reduced cytolysis to 30%. Recovery of GSH synthetic capacity after BSO treatment correlated with loss of the synergistic effect of BSO on lysis by vernolepin. BSO did not augment cytolysis by six other antineoplastics (doxorubicin, mitomycin C, vinblastine, cytosine arabinoside, maytansine, and 1,3-bis-[2-chloroethyl]-1-nitrosourea [BCNU]). Of these, only BCNU depleted cellular GSH. Lysis by jatrophone, another GSH-depleting antitumor agent, was increased 21-fold by BSO. Since prolonged incubation with BSO alone results in near-complete GSH depletion without loss of cell viability, SL-mediated cytolysis is probably not a result of GSH depletion. We have demonstrated, however, a critical role for GSH synthetic capacity as a determinant of tumor cell susceptibility to cytolysis by SL. GSH also plays an important role in cellular defense against oxidative injury. Vernolepin, acting as a GSH-depleting agent, markedly sensitized tumor cells to lysis by H2O2 (greater than 6.5-fold increase with 20 micrograms/ml of vernolepin). These findings suggest the possibility that the coordinated deployment of sulfhydryl-reactive antitumor agents, BSO, and oxidative injury might constitute an effective chemotherapeutic strategy.
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肿瘤抑制剂 vernolepin 使糖原合酶失活。
DOI：
10.1016/0005-2744(72)90011-3
发表时间：
1972
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
C. Smith;J. Larner,;A. M. Thomas;S. M. Kupchan
通讯作者：
S. M. Kupchan
DOI：
10.1073/pnas.78.12.7492
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
DETHMERS, JK;MEISTER, A
通讯作者：
MEISTER, A
半胱氨酸清除剂。
影响因子：
7.3
作者：
A. Rosowsky;N. Papathanasopoulos;H. Lazarus;G. Foley;E. Modest
通讯作者：
E. Modest
内源性谷胱甘肽对吞噬白细胞的保护：对谷胱甘肽还原酶缺乏症家庭的研究。
影响因子：
20.3
作者：
Dirk Roos;R. S. Weening;AA Voetman;M. V. Schaik;A. Bot;L. Meerhof;JA Loos
通讯作者：
JA Loos
生物硫醇与肿瘤抑制剂 jatrophone 的反应。
DOI：
10.1016/0005-2744(73)90106-x
发表时间：
1973
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
J. Lillehaug;K. Kleppe;C. W. Sigel;S. M. Kupchan
通讯作者：
S. M. Kupchan