Mitochondrial division inhibitor-1 potentiates cisplatin-induced apoptosis via the mitochondrial death pathway in cholangiocarcinoma cells - 16/02/19
, Tueanjai Khunluck b, Auemduan Prawan b, Laddawan Senggunprai b, Veerapol Kukongviriyapan b, cBienvenue sur EM-consulte, la référence des professionnels de santé.
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Graphical abstract |
Highlights |
• | Combination of mdivi-1 and cisplatin promotes oxidative stress in association with a decrease in GSH redox status and a loss of ∆Ψm. |
• | Mdivi-1 sensitizes cisplatin induced-apoptosis via the mitochondrial pathway by inhibiting anti-apoptotic Bcl-2 proteins. |
• | Mdivi-1 enhances cisplatin induced-cell death and suppresses migration of cholangiocarcinoma cells. |
Abstract |
Aims |
Mdivi-1, a selective Drp-1 inhibitor, impedes mitochondrial dynamics and suppresses cancer proliferation and progression. Cholangiocarcinoma (CCA) is a very aggressive malignancy which is refractory to chemotherapy. The study investigated the mechanism of the chemosensitizing effect of mdivi-1 in cholangiocarcinoma.
Main methods |
CCA cells and HEK293 T cells were employed in the study. Cell viability and induction of apoptotic cell death were determined by the MTT and acridine orange-ethidium bromide methods. Cellular glutathione content and reactive oxygen species (ROS) formation were assessed using thiol green and 2′,7′-dichlorofluorescin diacetate fluorescent probes, respectively. Mitochondrial transmembrane potential and autophagy were detected by JC-1 dye and autophagy assay. Cell cycle progression was analyzed by flow cytometry. Cell migration was measured using the wound healing assay. Proteins involved in cell proliferation and cell cycle were analyzed by western immunoblotting.
Key findings |
Mdivi-1 enhanced cisplatin-induced cytotoxicity in CCA cells but not in HEK293 T cells. Mdivi-1 enhanced cisplatin induced glutathione redox stress, ROS formation, and loss of mitochondrial transmembrane potential. Moreover, mdivi-1 also inhibited autophagic flux and suppressed CCA cell migration.
Significance |
Mdivi-1 sensitized CCA cells to cytotoxicity of cisplatin in association with increases of oxidative stress and autophagosomes, and induced cell death via the mitochondrial pathway. Disruption of mitochondrial dynamics may be a novel strategy to improve the efficacy of chemotherapy to treat CCA.
Le texte complet de cet article est disponible en PDF.Keywords : Cholangiocarcinoma, Cisplatin, Mdivi-1, Oxidative stress, Mitochondrial dysfunction
Plan
Vol 111
P. 109-118 - mars 2019 Retour au numéro
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