Synergistic antineoplastic action of 5-aza-2'deoxycytidine (decitabine) in combination with different inhibitors of enhancer of zeste homolog 2 (EZH2) on human lung carcinoma cells
| Autor: | Nascimento Asf, Momparler Rl, Yu J, Côté S, Jeong Ls |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
5-Aza-2'deoxycytidine/Decitabine 3-deazaneplanocin-A lcsh:Medicine macromolecular substances Human lung 03 medical and health sciences 0302 clinical medicine medicine Carcinoma antineoplastic action EZH2 5-aza-2'deoxycytidine DNA methylation epigenetics Chemistry lcsh:R medicine.disease Molecular biology lung cancer 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis U-4149 Cancer research Gsk-126 decitabine |
| Zdroj: | Journal of Cancer Research & Therapy, Vol 4, Iss 5, Pp 42-49 (2016) |
| ISSN: | 2052-4994 |
| DOI: | 10.14312/2052-4994.2016-8 |
| Popis: | Patients with metastatic lung cancer have a very poor prognosis indicating an urgent need to develop more effective chemotherapy. Aberrant promoter DNA methylation can result in the epigenetic silencing of tumor suppressor genes (TSGs) in lung cancer. 5-Aza-2’deoxycytidine (5-Aza-CdR, decitabine), an inhibitor of DNA methylation, is able to reactivate silent TSGs. Trimethylation of histone H3 on lysine 27 (H3K27me3) by enhancer of zeste homolog 2 (EZH2) histone methyltransferase can also silence TSGs in lung cancer. 3-Deazaneplanocin-A (DZNep), an inhibitor of EZH2, up-regulates the expression of genes silenced by H3K27me3. In this study we compared the in vitro antineoplastic activity of different inhibitors of EZH2; DZNep, U-4149 and Gsk-126, alone and in combination with 5-Aza-CdR, on the human A549 lung adenocarcinoma cells. U-4149, an analogue of DZNep, was more potent than either DZNep or Gsk-126. The reduction in colony formation was dose- and time-dependent for each EZH2 inhibitors. Combination treatment of 5-Aza-CdR with the EZH2 inhibitors showed a synergistic antineoplastic activity. 5-Aza-CdR and U-4149 was the most potent combination. The in vitro antineoplastic activity of these agents was evaluated by inhibition of growth, colony formation, induction of senescence and apoptosis. All the drug combinations induced signs of senescence and apoptosis. Analysis by gene expression by qRT-PCR showed that the combinations increased the expression of several TSGs to a greater extent that either agent alone. In conclusion, epigenetic therapy that specifically targets DNA and histone methylation has interesting potential for the treatment of lung cancer and merits further investigation. |
| Databáze: | OpenAIRE |
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