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A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
Enhanced chemosensitivity of drug-resistant osteosarcoma cells by lentivirus-mediated Bcl-2 silencing
Yao Zhao1, Chun-lin Zhang, Bing-fang Zeng
1Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200233, China.
Abstract:
The Bcl-2 gene is frequently overexpressed in malignancy and is responsible for the resistance induced by chemotherapeutic drugs. The aim of this study was to investigate whether the inhibition of Bcl-2 by lentivirus-mediated RNA interference would enhance doxorubicin cytotoxicity in the drug-resistant human osteosarcoma MG63 cells. Downregulation of Bcl-2 was confirmed by quantitative reverse transcription PCR and Western blotting. Moreover, the ratio of Bcl-2/Bax decreased due to the downregulation of Bcl-2 expression and the upregulation of Bax expression. Decreased cyclin D1 expression was also detected. Flow cytometry and MTT assays revealed that Bcl-2 knock-down increased cellular apoptosis and the MG63 cells became sensitive to doxorubicin. However, no detectable alterations in MDR1 or Bcl-xl expression were observed. Therefore, lentivirus-mediated Bcl-2 knock-down may sensitize these human osteosarcoma cells to doxorubicin and provide a potential therapeutic strategy for osteosarcoma.
Insights
Inhibiting the Bcl-2 gene using lentivirus-mediated RNA interference resensitized drug-resistant osteosarcoma cells to doxorubicin chemotherapy. This approach enhanced cell apoptosis and offers a potential new therapeutic strategy for osteosarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Bcl-2 gene overexpression is common in cancers, contributing to chemotherapy resistance.
- Osteosarcoma often exhibits resistance to chemotherapeutic drugs like doxorubicin.
- Targeting anti-apoptotic proteins like Bcl-2 is a strategy to overcome drug resistance.
Purpose of the Study:
- To investigate if inhibiting Bcl-2 via lentivirus-mediated RNA interference can enhance doxorubicin efficacy in drug-resistant human osteosarcoma MG63 cells.
- To assess the impact of Bcl-2 downregulation on apoptosis and chemosensitivity in osteosarcoma.
- To explore potential therapeutic strategies for overcoming doxorubicin resistance in osteosarcoma.
Main Methods:
- Lentivirus-mediated RNA interference was used to downregulate Bcl-2 expression in MG63 cells.
- Quantitative reverse transcription PCR and Western blotting confirmed Bcl-2 downregulation.
- Cellular apoptosis and chemosensitivity were evaluated using flow cytometry and MTT assays.
Main Results:
- Bcl-2 gene expression was successfully downregulated, decreasing the Bcl-2/Bax ratio and cyclin D1 levels.
- Knockdown of Bcl-2 significantly increased cellular apoptosis in MG63 cells.
- Osteosarcoma cells demonstrated increased sensitivity to doxorubicin following Bcl-2 inhibition, with no changes in MDR1 or Bcl-xl expression.
Conclusions:
- Lentivirus-mediated Bcl-2 knockdown effectively resensitizes drug-resistant human osteosarcoma cells to doxorubicin.
- This strategy modulates apoptosis-related protein expression, enhancing therapeutic outcomes.
- Targeting Bcl-2 represents a promising therapeutic avenue for osteosarcoma treatment.
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