Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione (GSH) is a ubiquitous non-protein thiol essential for cellular homeostasis and protection. Diazenecarboxamides (diazenes) are new compounds that could, according to their biochemical properties, lower the intracellular GSH content, thus inhibiting the growth of tumour cells. In the present study we examined four such compounds: JK-914, JK-918, JK-1013 and UP-91. Their cytotoxic effect on the growth of eight human tumour cell lines (glioblastoma, cervical and laryngeal carcinoma cells, mammary carcinoma cells and four drug-resistant sublines) was determined using a modified colorimetric MTT assay. The rate of reaction of thiophenol (as a model thiol) with diazenes leading to diphenyl disulfide was established by chromatography (TLC). Reactivity of diazenes with GSH under quasi-physiological conditions was determined by NMR spectroscopy. Intracellular GSH content was examined spectrophotometrically by the procedure developed by Tietze (1969). Diazene UP-91 reduced significantly the cell survival of all eight examined cell lines, including four drug-resistant cell lines. Other diazenes did not influence the survival of tumour cells. Reaction time for quantitative conversion of thiophenol to diphenyl disulfide was shortest for diazene UP-91, which is highly consistent with high reactivity of the same diazene with GSH, observed under quasi-physiological conditions. UP-91 reduced intracellular GSH level, while other diazenes had no effect on it. Thus, diazenecarboxamides UP-91 is a potential anticancer agent that may inhibit the growth of tumour cells due to reduction in glutathione level.
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PMID:Diazenecarboxamide UP-91, a potential anticancer agent, acts by reducing cellular glutathione content. 1257 33

We have previously synthesized various diazenecarboxamides (subsequently referred to as diazenes) that were cytotoxic to several tumor cell lines. To increase their biological activity, the structure has been modified appropriately. In the present study we examined the effects of N(1)-phenyl-N(2)-(2-pyridinylmethyl)diazenedicarboxamide (RL-337) obtained from the previously examined cytotoxic compound N(1)-phenyl-N(2)-(2-pyridinyl)diazenecarboxamide (JK-279), and compared them with those of diazene JK-279. Using a modified colorimetric MTT assay, the cytotoxicity of RL-337 was determined on human cervical carcinoma HeLa cells, glioblastoma A1235 cells, and prostate adenocarcinoma PC-3 cells. The possible synergistic effect of diazene RL-337 with cisplatin, doxorubicin, and vincristine, and its influence on intracellular GSH content was examined on HeLa cells. Diazene RL-337 was cytotoxic against all three human tumor cell lines, being more cytotoxic to HeLa cells than diazene JK-279. The higher efficacy of RL-337 than of JK-279 can be connected with higher basicity of the 2-picoline moiety present in the former diazene comparing with the pyridine fragment that is a part of the latter. The diazene RL-337 acted synergistically with cisplatin, doxorubicin, and vincristine (diazene JK-279 exhibited synergistic effect only with cisplatin). Glutathione (determined by Tietze's method) was not a target molecule of diazene RL-337 (but was for JK-279, as shown earlier). After just 1 h treatment with diazene RL-337, the cells started to lose membrane integrity. There was no cleavage of caspase-3 in RL-337-treated samples, and the majority of cells died 6 h after the treatment through necrosis (previously, apoptosis-like cell death was detected for diazene JK-279). Thus, although diazenes JK-279 and RL-337 are very similar in their structure, they exhibit widely different biological activity.
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PMID:Structurally similar diazenes exhibit significantly different biological activity. 1646 20