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https://www.arca.fiocruz.br/handle/icict/26043
XYLOPINE INDUCES OXIDATIVE STRESS AND CAUSES G2/M PHASE ARREST, TRIGGERING CASPASE-MEDIATED APOPTOSIS BY P53-INDEPENDENT PATHWAY IN HCT116 CELLS
Apoptose
Caspases
Alcalóides
Células HCT116
Carcinoma
Saúde pública
Neoplasia do colon
Apoptosis
Caspase
Alkaloid
HCT116 Cells
Carcinoma
Public health
Colon neoplasm
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Federal University of Sergipe. Department of Chemistry. São Cristóvão, SE, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Center of Biotechnology and Cell therapy. Salvador, BA, Brazil
Federal University of Amazonas. Department of Chemistry. Manaus, AM, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Federal University of Sergipe. Department of Chemistry. São Cristóvão, SE, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Hospital São Rafael. Center of Biotechnology and Cell therapy. Salvador, BA, Brazil
Federal University of Amazonas. Department of Chemistry. Manaus, AM, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil
Abstract
Xylopine is an aporphine alkaloid that has cytotoxic activity to cancer cells. In this study, the underlying mechanism of xylopine cytotoxicity was assessed in human colon carcinoma HCT116 cells. Xylopine displayed potent cytotoxicity in different cancer cell lines in monolayer cultures and in a 3D model of cancer multicellular spheroids formed from HCT116 cells. Typical morphology of apoptosis, cell cycle arrest in the G2/M phase, increased internucleosomal DNA fragmentation, loss of the mitochondrial transmembrane potential, and increased phosphatidylserine externalization and caspase-3 activation were observed in xylopine-treated HCT116 cells. Moreover, pretreatment with a caspase-3 inhibitor (Z-DEVD-FMK), but not with a p53 inhibitor (cyclic pifithrin-α), reduced xylopine-induced apoptosis, indicating induction of caspase-mediated apoptosis by the p53-independent pathway. Treatment with xylopine also caused an increase in the production of reactive oxygen/nitrogen species (ROS/RNS), including hydrogen peroxide and nitric oxide, but not superoxide anion, and reduced glutathione levels were decreased in xylopine-treated HCT116 cells. Application of the antioxidant N-acetylcysteine reduced the ROS levels and xylopine-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. In conclusion, xylopine has potent cytotoxicity to different cancer cell lines and is able to induce oxidative stress and G2/M phase arrest, triggering caspase-mediated apoptosis by the p53-independent pathway in HCT116 cells.
Keywords in Portuguese
Estresse oxidativoApoptose
Caspases
Alcalóides
Células HCT116
Carcinoma
Saúde pública
Neoplasia do colon
Keywords
Oxidative StressApoptosis
Caspase
Alkaloid
HCT116 Cells
Carcinoma
Public health
Colon neoplasm
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