Proapoptotic activity of Ukrain is based on Chelidonium majus L. alkaloids and mediated via a mitochondrial death pathway.

摘要: The anticancer drug Ukrain (NSC-631570) which has been specified by the manufacturer as semisynthetic derivative of Chelidonium majus L. alkaloid chelidonine and alkylans thiotepa was reported to exert selective cytotoxic effects on human tumour cell lines in vitro. Few clinical trials suggest beneficial treatment cancer. Aim present study elucidate importance apoptosis induction for antineoplastic activity Ukrain, define molecular mechanism its identify active constituents mass spectrometry. Apoptosis analysed a Jurkat T-lymphoma model fluorescence microscopy (chromatin condensation nuclear fragmentation), flow cytometry (cellular shrinkage, depolarisation mitochondrial membrane potential, caspase-activation) Western blot analysis (caspase-activation). Composition spectrometry LC-MS coupling. turned out be potent inducer apoptosis. Mechanistic analyses revealed that induced potential activation caspases. Lack caspase-8, expression cFLIP-L resistance death receptor ligand-induced failed inhibit Ukrain-induced while lack FADD caused delay but not abrogation pointing independent signalling pathway. In contrast, broad spectrum caspase-inhibitor zVAD-fmk blocked death. Moreover, over-expression Bcl-2 or Bcl-xL dominant negative caspase-9 partially reduced controlled events. However, spectrometric detect suggested trimeric thiophosphortriamide putative dimeric monomeric intermediates from chemical synthesis. Instead, alkaloids chelidonine, sanguinarine, chelerythrine, protopine allocryptopine were identified major components Ukrain. Apart sanguinarine triggering at concentrations 0.001 mM, less effective. Similar involved alterations caspase-activation. proapoptotic are due "Ukrain-molecule" efficacy including chelidonine.