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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
Novel agent DMAMCL suppresses osteosarcoma growth and decreases the stemness of osteosarcoma stem cell
Gen Ba1,2, Zhongyan Hua1,2, Ning Xu1,2
1Department of Pediatrics, Shengjing Hospital of China Medical University , Shenyang, China.
Abstract:
Osteosarcoma (OS) is the most common primary malignancy of bone that mostly affects children, adolescents, and young people. Despite advances have been made in multimodal therapy of OS, the long-term survival rate has reached a plateau, and the main obstacles are bad response to chemotherapy and gained chemoresistance. In this study, we tested the therapeutic effect of a newly reported drug, DMAMCL, on OS. Five human OS cell lines (143B, MNNG, MG63, Saos-2, U-2OS), and the mouse fibroblast cell line (NIH3T3) and human retinal epithelial cell (ARPE19) were used. The anti-tumor effect of DMAMCL was studied by MTS assay or IncuCyte-Zoom (in vitro), and Xenograft-mice-model (in vivo). Changes of cell cycle, apoptotic cells, caspase3/7 activities, and stemness after DMAMCL treatment were investigated. BAX siRNAs were used to knockdown the expression of BAX. Expressions of CyclinB1, CDC2, BCL-2 family, PARP, CD133, and Nanog were measured by Western Blotting. DMAMCL-induced dose-dependent OS cell death in vitro, and suppressed tumor growth and extended the survival of xenograft-bearing mice. DMAMCL-induced G2/M phase arrest in vitro, and apoptosis both in vitro and in vivo. Down-regulation of BAX expression attenuated the DMAMCL-induced OS cell death in vitro. We also found that DMAMCL inhibited the stemness in OS cells. These results indicated that DMAMCL possess therapeutic value in OS and may be a promising candidate for the new drug discovery for OS therapy.
Insights
A new drug, DMAMCL, effectively kills osteosarcoma (OS) cells and inhibits tumor growth in mice. DMAMCL induces cell death and apoptosis, offering a promising new therapeutic strategy for bone cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Osteosarcoma (OS) is a primary bone cancer predominantly affecting young individuals.
- Current multimodal therapies for OS have plateaued in improving long-term survival due to chemotherapy resistance.
- Novel therapeutic agents are crucial for overcoming treatment challenges in OS.
Purpose of the Study:
- To evaluate the therapeutic potential of a novel drug, DMAMCL, against osteosarcoma (OS).
- To investigate the in vitro and in vivo anti-tumor effects of DMAMCL on OS.
- To elucidate the mechanisms underlying DMAMCL's action, including cell cycle, apoptosis, and stemness.
Main Methods:
- DMAMCL's anti-tumor efficacy was assessed using MTS assays and IncuCyte-Zoom (in vitro) and a xenograft mouse model (in vivo).
- Cell cycle progression, apoptosis, caspase activity, and stemness markers were analyzed post-DMAMCL treatment.
- Western blotting and siRNA-mediated knockdown of BAX were employed to study molecular mechanisms.
Main Results:
- DMAMCL demonstrated dose-dependent induction of cell death in human OS cell lines in vitro.
- DMAMCL suppressed tumor growth and prolonged survival in xenograft-bearing mice.
- DMAMCL induced G2/M phase arrest, apoptosis, and inhibited stemness in OS cells, with BAX downregulation partially rescuing cell death.
Conclusions:
- DMAMCL exhibits significant therapeutic value against osteosarcoma.
- DMAMCL's mechanisms involve inducing apoptosis and inhibiting cancer stemness.
- DMAMCL represents a promising candidate for novel drug discovery in osteosarcoma treatment.
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