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Published on: March 18, 2014
Iron Chelator Induces Apoptosis in Osteosarcoma Cells by Disrupting Intracellular Iron Homeostasis and Activating the
Yanru Xue1,2,3, Gejing Zhang1,2,3, Shoujie Zhou1,2,3
1School of Life Science, Northwestern Polytechnical University, Xi'an 710072, China.
Abstract:
Osteosarcoma is a common malignant bone tumor in clinical orthopedics. Iron chelators have inhibitory effects on many cancers, but their effects and mechanisms in osteosarcoma are still uncertain. Our in vitro results show that deferoxamine (DFO) and deferasirox (DFX), two iron chelators, significantly inhibited the proliferation of osteosarcoma cells (MG-63, MNNG/HOS and K7M2). The viability of osteosarcoma cells was decreased by DFO and DFX in a concentration-dependent manner. DFO and DFX generated reactive oxygen species (ROS), altered iron metabolism and triggered apoptosis in osteosarcoma cells. Iron chelator-induced apoptosis was due to the activation of the MAPK signaling pathway, with increased phosphorylation levels of JNK, p38 and ERK, and ROS generation; in this process, the expression of C-caspase-3 and C-PARP increased. In an orthotopic osteosarcoma transplantation model, iron chelators (20 mg/kg every day, Ip, for 14 days) significantly inhibited the growth of the tumor. Immunohistochemical analysis showed that iron metabolism was altered, apoptosis was promoted, and malignant proliferation was reduced with iron chelators in the tumor tissues. In conclusion, we observed that iron chelators induced apoptosis in osteosarcoma by activating the ROS-related MAPK signaling pathway. Because iron is crucial for cell proliferation, iron chelators may provide a novel therapeutic strategy for osteosarcoma.
Insights
Iron chelators like deferoxamine and deferasirox inhibit osteosarcoma cell growth by triggering apoptosis through the ROS-related MAPK pathway. These findings suggest iron chelators as a potential novel therapy for osteosarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Osteosarcoma is a prevalent malignant bone tumor.
- The therapeutic potential and mechanisms of iron chelators in osteosarcoma remain unclear.
- Iron is essential for cell proliferation, making its metabolism a target for cancer therapy.
Purpose of the Study:
- To investigate the effects and mechanisms of iron chelators deferoxamine (DFO) and deferasirox (DFX) on osteosarcoma cells.
- To explore the role of reactive oxygen species (ROS) and the MAPK signaling pathway in iron chelator-induced apoptosis.
- To evaluate the in vivo efficacy of iron chelators in an osteosarcoma transplantation model.
Main Methods:
- In vitro studies using osteosarcoma cell lines (MG-63, MNNG/HOS, K7M2) treated with DFO and DFX.
- Assessment of cell proliferation, viability, ROS generation, iron metabolism, and apoptosis.
- Analysis of MAPK signaling pathway activation (JNK, p38, ERK phosphorylation) and apoptosis-related protein expression (C-caspase-3, C-PARP).
- In vivo experiments using an orthotopic osteosarcoma transplantation model in mice.
Main Results:
- DFO and DFX significantly inhibited osteosarcoma cell proliferation and viability in a dose-dependent manner.
- Iron chelators induced ROS generation, altered iron metabolism, and triggered apoptosis in osteosarcoma cells.
- Apoptosis was mediated by the activation of the ROS-related MAPK signaling pathway, evidenced by increased phosphorylation of JNK, p38, and ERK, and elevated C-caspase-3 and C-PARP levels.
- In vivo, iron chelators significantly suppressed tumor growth, reduced malignant proliferation, and promoted apoptosis in tumor tissues.
Conclusions:
- Iron chelators effectively induce apoptosis in osteosarcoma cells through the ROS-mediated activation of the MAPK signaling pathway.
- Iron chelators demonstrate significant anti-tumor effects in both in vitro and in vivo osteosarcoma models.
- Targeting iron metabolism with iron chelators represents a promising novel therapeutic strategy for osteosarcoma.
