engleski

Incorporation of a N-methyleneamido group to N1-phenyl-N2-(2-pyridinyl)diazenecarboxamide induces necrosis instead of apoptosis-like cell death

We have synthesised various diazenecarboxamides (shortly diazenes) that were cytotoxic to several tumor cell lines. To increase their solubility and biological activity, the structure has been properly modified. In the present study we examined the biological activity of N1-phenyl-N2-(2-pyridinylmethyl)diazenedicarboxamide (RL-337) and compare it to already examined cytotoxic compound N1-phenyl-N2-(2-pyridinyl)diazenecarboxamide (JK-279) that possesses similar structure. 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 (determined by Tietze’ s method) 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. Higher efficacy of RL-337 with regard to JK-279 can be connected with a higher basicity of the 2-picoline moiety, present in the former diazene, comparing with the pyridine fragment that is a part of the latter one. The diazene RL-337 acted synergistically with cisplatin, doxorubicine and vincristine, while diazene JK-279 exhibited synergistic effect only with cisplatin. Glutathione was not a target molecule of diazene RL-337, but was for JK-279, as shown earlier. After just one hour of treatment with diazene RL-337, the cells started to loose membrane integrity, suggesting necrosis as possible mechanism of cytotoxicity, while previously for diazene JK-279 apoptosis-like cell death was detected. Thus, although diazenes JK-279 and RL-337 are very similar in their structure, they exhibited largely different biological activity.

diazenes; apoptosis; necrosis

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