1. ABT-263 enhances sorafenib-induced apoptosis associated with Akt activity and the expression of Bax and p21((CIP1/WAF1)) in human cancer cells.
- Author
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Li J, Chen Y, Wan J, Liu X, Yu C, and Li W
- Subjects
- Aniline Compounds administration & dosage, Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Blotting, Western, Cell Line, Tumor, Cell Survival drug effects, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Drug Synergism, Humans, In Situ Nick-End Labeling, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasms pathology, Niacinamide administration & dosage, Niacinamide pharmacology, Phenylurea Compounds administration & dosage, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, Reactive Oxygen Species metabolism, Sorafenib, Sulfonamides administration & dosage, Xenograft Model Antitumor Assays, bcl-2-Associated X Protein genetics, bcl-2-Associated X Protein metabolism, Aniline Compounds pharmacology, Apoptosis drug effects, Neoplasms drug therapy, Niacinamide analogs & derivatives, Phenylurea Compounds pharmacology, Sulfonamides pharmacology
- Abstract
Background and Purpose: Sorafenib, a potent inhibitor that targets several kinases associated with tumourigenesis and cell survival, has been approved for clinical treatment as a single agent. However, combining sorafenib with other agents improves its anti-tumour efficacy in various preclinical tumour models. ABT-263, a second-generation BH3 mimic, binds to the anti-apoptotic family members Bcl-2, Bcl-xL and Bcl-w, and has been demonstrated to enhance TNFSF10 (TRAIL)-induced apoptosis in human hepatocarcinoma cells. Hence, we investigated the effects of ABT-263 treatment combined with sorafenib., Experimental Approach: The effects of ABT-263 combined with sorafenib were investigated in vitro, on cell viability, clone formation and apoptosis, and the mechanism examined using western blot and flow cytometry. This combination was also evaluated in vivo, in a mouse xenograft model; tumour growth, volume and weights were measured and a TUNEL assay performed., Key Results: ABT-263 enhanced sorafenib-induced apoptosis while sparing non-tumourigenic cells. Although ABT-263 plus sorafenib significantly stimulated intracellular reactive oxygen species production and subsequent mitochondrial depolarization, this was not sufficient to trigger cell apoptosis. ABT-263 plus sorafenib significantly decreased Akt activity, which was, at least partly, involved in its effect on apoptosis. Bax and p21 (CIP1/WAF1) were shown to play a critical role in ABT-263 plus sorafenib-induced apoptosis. Combining sorafenib with ABT-263 dramatically increased its efficacy in vivo., Conclusion and Implications: The anti-tumour activity of ABT-263 plus sorafenib may involve the induction of intrinsic cell apoptosis via inhibition of Akt, and reduced Bax and p21 expression. Our findings offer a novel effective therapeutic strategy for tumour treatment., (© 2014 The British Pharmacological Society.)
- Published
- 2014
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