Curcumin overcome primary gefitinib resistance in non-small-cell lung cancer cells through inducing autophagy-related cell death
| العنوان: | Curcumin overcome primary gefitinib resistance in non-small-cell lung cancer cells through inducing autophagy-related cell death |
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| المؤلفون: | Chen-Guo Chen, Jun Jin, Yi Wang, Wei-Guo Long, Kan Chen, Xiaohui Zhao, Han-Peng Huang, Ping Chen, Jian Li |
| المصدر: | Journal of Experimental & Clinical Cancer Research : CR Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-17 (2019) |
| بيانات النشر: | BioMed Central, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, MAPK/ERK pathway, Cancer Research, Lung Neoplasms, Resistance, Receptor tyrosine kinase, chemistry.chemical_compound, Mice, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Epidermal growth factor receptor, biology, Gefitinib, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, ErbB Receptors, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Female, Tyrosine kinase, medicine.drug, Protein Binding, Signal Transduction, Programmed cell death, Curcumin, Cell Survival, Antineoplastic Agents, Tyrosine kinase inhibitor (TKI), lcsh:RC254-282, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Cell Line, Tumor, medicine, Autophagy, Animals, Humans, neoplasms, Research, Epidermal growth factor receptor (EGFR), respiratory tract diseases, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Mutation, Cancer research, biology.protein, Non-small-cell lung cancer |
| الوصف: | Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are being wildly used as target therapy in non-small-cell lung cancer (NSCLC). However, NSCLC patients with wild-type EGFR and KRAS mutation are primary resistant to EGFR-TKIs such as gefitinib. Curcumin has been known as a potential therapeutic agent for several major human cancers. In this study, we investigated the effect of curcumin on the reversal of gefitinib resistance in NSCLC cells as well as their molecular bases. Methods H157 (wild-type EGFR and KARS mutation) and H1299 (wild-type EGFR and HRAS mutation) cells were treated with gefitinib or curcumin alone, or the two combination, and then cell viability, EGFR activity, expressions of Sp1 and Sp1-dependent proteins and receptor tyrosine kinases, markers of autophagy and apoptosis were examined by using CCK-8, colony formation, immunoblot, quantitative PCR, immunofluoscence, and flow cytometry assays. Also xenograft experiments were conduced to test the synergism of curcumin to gefitinib. Results Our results showed that curcumin significantly enhanced inhibitory effect of gefitinib on primary gefitinib-resistant NSCLC cell lines H157 and H1299. Combination treatment with curcumin and gefitinib markedly downregulated EGFR activity through suppressing Sp1 and blocking interaction of Sp1 and HADC1, and markedly suppressed receptor tyrosine kinases as well as ERK/MEK and AKT/S6K pathways in the resistant NSCLC cells. Meanwhile, combination treatment of curcumin and gefitinib caused dramatic autophagy induction, autophagic cell death and autophagy-mediated apoptosis, compared to curcumin or gefitinib treatment alone, as evidenced by the findings that curcumin and gefitinib combination treatment-produced synergistic growth inhibition and apoptosis activation can be reversed by pharmacological autophagy inhibitors (Baf A1 or 3-MA) or knockdown of Beclin-1 or ATG7, also can be partially returned by pan-caspase inhibitor (Z-VAD-FMK) in H157 and H1299 cells. Xenograft experiments in vivo yielded similar results. Conclusions These data indicate that the synergism of curcumin on gefitinib was autophagy dependent. Curcumin can be used as a sensitizer to enhance the efficacy of EGFR-TKIs and overcome the EGFR-TKI resistance in NSCLC patients with wild-type EGFR and/or KRAS mutation. Electronic supplementary material The online version of this article (10.1186/s13046-019-1234-8) contains supplementary material, which is available to authorized users. |
| اللغة: | English |
| تدمد: | 1756-9966 0392-9078 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2a592e1baa1cc3f3b4eaf25f7fbd4206 http://europepmc.org/articles/PMC6567416 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....2a592e1baa1cc3f3b4eaf25f7fbd4206 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 17569966 03929078 |
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