Aspirin overcomes Navitoclax-resistance in hepatocellular carcinoma cells through suppression of Mcl-1
Autor: | Yongfu Zhao, Gongquan Li, Hongbo Fang, Xue-Xiang Ye, Xiuxian Ma, Bing Yan, Shuijun Zhang, Liu-Shun Feng |
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Rok vydání: | 2013 |
Předmět: |
Carcinoma
Hepatocellular Cell Survival Poly ADP ribose polymerase Blotting Western Biophysics Antineoplastic Agents Apoptosis Cysteine Proteinase Inhibitors Pharmacology Biochemistry chemistry.chemical_compound Cell Line Tumor medicine Humans Viability assay Molecular Biology Sulfonamides Aspirin Aniline Compounds Navitoclax Dose-Response Relationship Drug biology Caspase 3 Effector business.industry Cytochrome c Anti-Inflammatory Agents Non-Steroidal Liver Neoplasms Cytochromes c Cancer Drug Synergism Hep G2 Cells Cell Biology medicine.disease Caspase 9 Proto-Oncogene Proteins c-bcl-2 chemistry Drug Resistance Neoplasm Hepatocellular carcinoma biology.protein Myeloid Cell Leukemia Sequence 1 Protein RNA Interference business Oligopeptides medicine.drug |
Zdroj: | Biochemical and Biophysical Research Communications. 434:809-814 |
ISSN: | 0006-291X |
DOI: | 10.1016/j.bbrc.2013.04.018 |
Popis: | Small-molecule Bcl-2/Bcl-xL inhibitor Navitoclax represents a promising cancer therapeutic since preclinical and clinical studies with Navitoclax have demonstrated strong anticancer activity in several types of cancers. However, because Navitoclax has a low binding affinity to Mcl-1, anticancer activity by Navitoclax is often attenuated by the elevated expression of Mcl-1 in hepatocellular carcinoma (HCC) and other cancers, posing a serious problem for its potential clinical utilities. Therefore, approaches that suppress the expression of Mcl-1 are urgently needed to overcome Navitoclax-resistance in these cancers. Here, we reported that aspirin markedly suppressed Mcl-1 expression, and significantly enhanced Navitoclax-mediated cell viability inhibition and apoptosis induction in HCC cells. We further showed that aspirin robustly enhanced Navitoclax-triggered cytosolic cytochrome c release, activation of initiator caspase-9 and effector caspase-3, and cleavage of PARP. Importantly, the cell death induction by the combination could be rescued by a cell-permeable caspase-9 inhibitor Z-LEHD-FMK, indicative of an indispensable role of mitochondrial apoptosis pathway during the combination effect. Taken together, our study suggests that aspirin can be used to enhance Navitoclax-mediated anticancer activity via suppression of Mcl-1. Since aspirin is one of the most commonly used medicines, our findings therefore have translational impacts on Navitoclax-based therapy for HCC. |
Databáze: | OpenAIRE |
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