Synergistic increase in efficacy of a combination of 2-deoxy-d-glucose and cisplatin in normoxia and hypoxia: switch from autophagy to apoptosis
| العنوان: | Synergistic increase in efficacy of a combination of 2-deoxy-d-glucose and cisplatin in normoxia and hypoxia: switch from autophagy to apoptosis |
|---|---|
| المؤلفون: | Bhudev C. Das, Akansha Jalota, Kunzang Chosdol, Subrata Sinha, Ajay Yadav, Mukesh Kumar |
| المصدر: | Tumor Biology. 37:12347-12358 |
| بيانات النشر: | Springer Science and Business Media LLC, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Cell Survival, Morpholines, Blotting, Western, Gene Expression, Antineoplastic Agents, Apoptosis, Deoxyglucose, Pharmacology, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Line, Tumor, Glioma, Autophagy, Temozolomide, medicine, Humans, LY294002, Viability assay, Protein kinase B, bcl-2-Associated X Protein, Cisplatin, Dose-Response Relationship, Drug, Reverse Transcriptase Polymerase Chain Reaction, Drug Synergism, General Medicine, Hypoxia (medical), Flow Cytometry, medicine.disease, Cell Hypoxia, Dacarbazine, Oxygen, 030104 developmental biology, chemistry, Chromones, 030220 oncology & carcinogenesis, medicine.symptom, Glioblastoma, Proto-Oncogene Proteins c-akt, medicine.drug |
| الوصف: | Resistance to drugs, which is aggravated by hypoxia, is a well-known feature of tumors. The combination of drug exposure and hypoxia can give rise to several survival strategies in the exposed cells. Glioblastoma multiforme (GBM) is among the most hypoxic of solid tumors, and we have used glial cells to identify a drug combination that would be synergistically effective in these cells under both normoxia and hypoxia. Cisplatin (CP) and 2-deoxy-D-glucose (2-DG), which have been used for second-line therapy and for preclinical research, are relatively ineffective as single agents. During in vitro experiments with A172 and LN229 cells, there was increased resistance to both drugs under hypoxia. However, the combination of CP and 2-DG showed a synergistic effect in reducing cell viability under both normoxia and hypoxia, with a combination index of less than 1. Increased autophagy is a distinct feature of the response to 2-DG. However, autophagic markers were reduced, and apoptotic markers were upregulated by the combination, indicating a switch over from autophagic to apoptotic pathways with reduction in endoplasmic reticulum (ER) stress. The combination also resulted in a decrease of pAKT levels. The effect of CP in the combination was replicated by the prototype AKT inhibitor LY294002, further supporting the role of AKT inhibition in the synergism. Combination of 2-DG with CP, or possibly an AKT inhibitor, can prove to be an effective rational combination for reducing chemoresistance under both normoxic and hypoxic conditions in gliomas. |
| تدمد: | 1423-0380 1010-4283 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::792c9b809ef4607bf4fd53ab671a52f9Test https://doi.org/10.1007/s13277-016-5089-8Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....792c9b809ef4607bf4fd53ab671a52f9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14230380 10104283 |
|---|