Scoulerine is an isoquinoline alkaloid, which indicated promising suppression of cancer cells growth. However, the mode of action (MOA) remained unclear. Cytotoxic and antiproliferative properties were determined in this study. Scoulerine reduces the mitochondrial dehydrogenases activity of the evaluated leukemic cells with IC50 values ranging from 2.7 to 6.5 µM. The xCELLigence system revealed that scoulerine exerted potent antiproliferative activity in lung, ovarian and breast carcinoma cell lines. Jurkat and MOLT-4 leukemic cells treated with scoulerine were decreased in proliferation and viability. Scoulerine acted to inhibit proliferation through inducing G2 or M-phase cell cycle arrest, which correlates well with the observed breakdown of the microtubule network, increased Chk1 Ser345, Chk2 Thr68 and mitotic H3 Ser10 phosphorylation. Scoulerine was able to activate apoptosis, as determined by p53 upregulation, increase caspase activity, Annexin V and TUNEL labeling. Results highlight the potent antiproliferative and proapoptotic function of scoulerine in cancer cells caused by its ability to interfere with the microtubule elements of the cytoskeleton, checkpoint kinase signaling and p53 proteins. This is the first study of the mechanism of scoulerine at cellular and molecular level. Scoulerine is a potent antimitotic compound and that it merits further investigation as an anticancer drug.
- MeSH
- aktivace enzymů účinky léků MeSH
- antitumorózní látky chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- berberinové alkaloidy chemie farmakologie MeSH
- estery chemie MeSH
- fosforylace účinky léků MeSH
- kaspasy metabolismus MeSH
- kontrolní body buněčného cyklu účinky léků MeSH
- kyseliny karboxylové chemie MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- mikrotubuly účinky léků metabolismus MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- signální transdukce účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zlomy DNA účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
DNA repair in blood cells was observed to be suboptimal in cancer patients at diagnosis, including colorectal cancer (CRC). To explore the causality of this phenomenon, we studied the dynamics of DNA repair from diagnosis to 1 yr follow-up, and with respect to CRC treatment. Systemic CRC therapy is targeted to DNA damage induction and DNA repair is thus of interest. CRC patients were blood-sampled three times in 6-mo intervals, starting at the diagnosis, and compared to healthy controls. DNA repair was characterized by mRNA levels of 40 repair genes, by capacity of nucleotide excision repair (NER), and by levels of DNA strand breaks (SBs). NER and base excision repair genes were significantly under-expressed (P < 0.016) in patients at diagnosis compared to controls, in accordance with reduced NER function (P = 0.008) and increased SBs (P = 0.015). Six months later, there was an increase of NER capacity, but not of gene expression levels, in treated patients only. A year from diagnosis, gene expression profiles and NER capacity were significantly modified in all patients and were no longer different from those measured in controls. All patients were free of relapse at the last sampling, so we were unable to clarify the impact of DNA repair parameters on treatment response. However, we identified a panel of blood DNA repair-related markers discerning acute stage of the disease from the remission period. In conclusion, our results support a model in which DNA repair is altered as a result of cancer.
- MeSH
- antitumorózní látky terapeutické užití MeSH
- kolon účinky léků metabolismus MeSH
- kolorektální nádory krev farmakoterapie genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- oprava DNA * účinky léků MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- rektum účinky léků metabolismus MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- zlomy DNA účinky léků MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH