Identification of JNK1 as a predicting biomarker for ABT-199 and paclitaxel combination treatment
| Autor: | Minhang Zhang, Yudan Fan, Zhenyu Xue, Peng Liu, Ting Song, Zhichao Zhang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Paclitaxel Cell Survival Antineoplastic Agents HL-60 Cells Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Breast cancer Predictive Value of Tests Biomarkers Tumor medicine Humans Mitogen-Activated Protein Kinase 8 Lung cancer Pharmacology Sulfonamides Dose-Response Relationship Drug Venetoclax business.industry Bridged Bicyclo Compounds Heterocyclic medicine.disease Antineoplastic Agents Phytogenic Leukemia 030104 developmental biology chemistry A549 Cells 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells Cancer research Biomarker (medicine) Drug Therapy Combination Ovarian cancer business HeLa Cells |
| Zdroj: | Biochemical Pharmacology. 155:102-109 |
| ISSN: | 0006-2952 |
| Popis: | Targeting Bcl-2 with ABT-199 (Venetoclax) shows limited single-agent activity against many cancers in both preclinical and clinical investigations. Combination therapies have attracted great attention. The principal purpose of this study was to investigate the mechanism of synergism between ABT-199 and paclitaxel. Moreover, we analyzed the biomarker to identify tumors which are most likely to respond to this combination. We evaluated the effect of this combination in a panel of nine cancer cell lines including cervical cancer, lung cancer, ovarian cancer, lymphoma, leukemia and breast cancer. Combination index (CI) assay showed that four of nine call lines exhibited synergistic respond to ABT-199/paclitaxel combination due to enhanced intrinsic apoptosis. However, paclitaxel-induced Bcl-2 phosphorylation impaired the synergistic effect by impeding the freeing of Bax and Bim by ABT-199 because ABT-199 cannot hit phosphorylated Bcl-2 (pBcl-2). By means of a correlation analysis of JNK level with CI value in combination with overexpressing or silencing JNK protein in cancer cells, we identified basal JNK1 level as a potential biomarker for predicting the level of pBcl-2 upon paclitaxel treatment, and thus for predicting a synergistic response. A cut-off value of 0.37 for relative JNK1 expression level was determined using receiver operating characteristic (ROC) analysis to distinguish between synergistic and non-synergistic response cancers. A more accurate and valid cut-off value for JNK1 will be gained based on a large-scale clinical samples analysis. |
| Databáze: | OpenAIRE |
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