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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
Oncolytic adenovirus‑mediated mda‑7/IL‑24 expression suppresses osteosarcoma growth and enhances sensitivity to
Zongming Liu1, Libo Xu2, Hongping Yuan3
1Department of Anesthesiology, Jilin Cancer Hospital, Changchun, Jilin 130000, P.R. China.
Abstract:
Osteosarcoma (OS) is a malignant disease with a high mortality rate and poor response to current chemotherapy. Melanoma differentiation associated gene‑7 (Mda7)/interleukin (IL)‑24 has been demonstrated to suppress the growth of OS. However, the expression level of Mda7/IL‑24 mediated by the current adenoviral vector is limited for effective clinical treatment of OS. In order to solve this issue, an oncolytic adenovirus was employed to express IL‑24 (OA‑IL‑24) in OS cells. Quantitative polymerase chain reaction, immunoblot and ELISA assays verified that OA‑IL‑24 expressed IL‑24 at a higher level than the replication‑deficient adenoviral vector, Ad‑IL24. OA‑IL‑24 infection led to decreased cell viability and increased apoptosis of OS cells, compared with Ad‑IL‑24. Animal studies further confirmed the increased anti‑tumor activity of OA‑IL‑24. Notably, OA‑IL‑24 was also found to sensitize OS cells to doxorubicin. OA‑IL‑24‑induced multiple drug resistance reversion was associated with reduced expression of Pgp and BCRP1, as well as minimized autophagy. Furthermore, restoring Pgp and BCRP1 expression as well as autophagy, was able to rescue the effect of IL‑24 on the cytotoxicity of doxorubicin to OS. In conclusion, a method for inducing a high expression of IL‑24 in OS was provided. In addition, IL‑24 was demonstrated to increase the sensitivity of OS to doxorubicin.
Insights
A novel oncolytic adenovirus expressing interleukin-24 (OA-IL-24) effectively suppresses osteosarcoma growth and enhances doxorubicin sensitivity by reducing drug resistance mechanisms.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Osteosarcoma (OS) is a highly lethal cancer with limited treatment options.
- Melanoma differentiation associated gene-7 (Mda7)/interleukin (IL)-24 shows potential in suppressing OS growth.
- Current adenoviral vectors provide insufficient IL-24 expression for effective OS treatment.
Purpose of the Study:
- To develop an oncolytic adenovirus (OA-IL-24) for high-level IL-24 expression in OS cells.
- To evaluate the anti-tumor efficacy of OA-IL-24 in OS.
- To investigate OA-IL-24's role in sensitizing OS to doxorubicin.
Main Methods:
- Utilized an oncolytic adenovirus to express IL-24 (OA-IL-24) in OS cells.
- Employed quantitative PCR, immunoblot, and ELISA to verify IL-24 expression levels.
- Assessed cell viability, apoptosis, and anti-tumor activity in vitro and in vivo.
- Investigated mechanisms of drug resistance reversion, including Pgp, BCRP1, and autophagy.
Main Results:
- OA-IL-24 achieved significantly higher IL-24 expression compared to Ad-IL24.
- OA-IL-24 demonstrated superior inhibition of OS cell viability and enhanced apoptosis.
- In vivo studies confirmed OA-IL-24's potent anti-tumor activity.
- OA-IL-24 sensitized OS cells to doxorubicin by downregulating Pgp, BCRP1, and autophagy.
Conclusions:
- Developed a method for high-level IL-24 induction in osteosarcoma.
- OA-IL-24 exhibits significant anti-tumor effects and enhances doxorubicin efficacy in OS.
- IL-24's sensitization of OS to doxorubicin is linked to reduced Pgp, BCRP1, and autophagy.
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