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Published on: March 18, 2019
Downregulation of c-jun results in apoptosis-mediated anti-osteosarcoma activity in an orthotopic model
Crispin R Dass1, Anna M Friedhuber, Levon M Khachigian
1Department of Orthopaedics and University of Melbourne Department of Surgery, St. Vincent's Hospital, Victoria, Australia. cris.dass@yahoo.com
Abstract:
c-jun has been found to be upregulated in a variety of cancers including osteosarcoma. DNAzymes are oligonucleotides capable of specific downregulation of target genes. c-jun knockdown-mediated apoptosis in osteosarcoma cells involved caspases-1, -2 and -8, but not the Fas/FasL pathway. A c-jun DNAzyme, encapsulated within a novel cationic multilamellar vesicle liposome, inhibited the growth and metastasis of osteosarcoma in an orthotopic spontaneously metastasising model of the disease. The 60 nm DDAB:DOPE liposome was formulated using ethanol injection/extrusion. Clinically, downregulation of c-jun may proffer an improved treatment outcome for these tumours originating in bone.
Insights
Downregulating c-jun with a novel DNAzyme liposome inhibits osteosarcoma growth and metastasis. This targeted approach may improve treatment outcomes for bone cancers by inducing apoptosis via specific caspase pathways.
Area of Science:
- Oncology
- Molecular Biology
- Nanotechnology
Background:
- c-jun is upregulated in various cancers, including osteosarcoma.
- DNAzymes offer targeted gene downregulation.
- Osteosarcoma bone tumors require novel therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of a c-jun DNAzyme delivered via a novel liposome for osteosarcoma treatment.
- To elucidate the apoptotic pathways involved in c-jun knockdown in osteosarcoma cells.
Main Methods:
- Formulation of a 60 nm cationic multilamellar vesicle liposome (DDAB:DOPE) using ethanol injection/extrusion.
- Encapsulation of a c-jun DNAzyme within the liposome.
- Evaluation in an orthotopic, spontaneously metastasizing osteosarcoma model.
Main Results:
- The c-jun DNAzyme liposome significantly inhibited osteosarcoma growth and metastasis.
- c-jun knockdown induced apoptosis through caspases-1, -2, and -8, independent of the Fas/FasL pathway.
- The liposome formulation was stable and effectively delivered the DNAzyme.
Conclusions:
- Targeted c-jun downregulation using DNAzyme-loaded liposomes is a promising therapeutic strategy for osteosarcoma.
- This approach effectively suppresses tumor growth and metastasis while inducing cancer cell apoptosis.
- Further clinical investigation is warranted to assess treatment outcomes for bone tumors.
