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SF2523 inhibits human chondrosarcoma cell growth in vitro and in vivo
1Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Abstract:
Developing novel therapeutic agents against chondrosarcoma is important. SF2523 is a PI3K-Akt-mTOR and bromodomain-containing protein 4 (BRD4) dual inhibitor. Its activity in human chondrosarcoma cells is tested. Our results show that SF2523 potently inhibited survival, proliferation and migration, and induced apoptosis activation in SW1353 cells and primary human chondrosarcoma cells. The dual inhibitor was yet non-cytotoxic to the primary human osteoblasts and OB-6 osteoblastic cells. SF2523 blocked Akt-mTOR activation and downregulated BRD4-regulated genes (Bcl-2 and c-Myc) in chondrosarcoma cells. It was more efficient in killing chondrosarcoma cells than other established PI3K-Akt-mTOR and BRD4 inhibitors, including JQ1, perifosine and OSI-027. In vivo, intraperitoneal injection of SF2523 (30 mg/kg) potently inhibited subcutaneous SW1353 xenograft tumor growth in severe combined immunodeficient mice. Akt-mTOR inhibition as well as Bcl-2 and c-Myc downregulation were detected in SF2523-treated SW1353 tumor tissues. In conclusion, targeting PI3K-Akt-mTOR and BRD4 by SF2523 potently inhibited chondrosarcoma cell growth in vitro and in vivo.
Insights
SF2523, a dual inhibitor of PI3K-Akt-mTOR and BRD4, effectively suppressed chondrosarcoma cell growth, survival, and migration while inducing apoptosis. This novel agent demonstrated potent anti-tumor activity in vitro and in vivo without harming healthy bone cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chondrosarcoma is a rare bone cancer with limited effective therapeutic options.
- Targeting the PI3K-Akt-mTOR and bromodomain-containing protein 4 (BRD4) pathways presents a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the efficacy of SF252523, a novel dual inhibitor, against human chondrosarcoma cells.
- To investigate the molecular mechanisms underlying SF2523's anti-cancer effects.
Main Methods:
- In vitro studies using SW1353 and primary human chondrosarcoma cells.
- In vivo studies using subcutaneous SW1353 xenograft models in immunodeficient mice.
- Assessment of cell viability, proliferation, migration, apoptosis, and molecular targets (Akt-mTOR, BRD4-regulated genes).
Main Results:
- SF2523 potently inhibited chondrosarcoma cell survival, proliferation, and migration, while inducing apoptosis.
- SF2523 demonstrated selective toxicity, sparing normal osteoblasts.
- In vivo, SF2523 significantly inhibited tumor growth and confirmed pathway inhibition in tumor tissues.
Conclusions:
- SF2523 is a potent dual inhibitor of PI3K-Akt-mTOR and BRD4 with significant anti-chondrosarcoma activity.
- SF2523 represents a promising therapeutic candidate for chondrosarcoma treatment.
- Targeting both PI3K-Akt-mTOR and BRD4 pathways offers a viable strategy for chondrosarcoma therapy.
