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Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
FIM-A, a phosphorus-containing sirolimus, inhibits the angiogenesis and proliferation of osteosarcomas
Wei-Nan Liu1, Jian-Hua Lin, Yuan-Rong Cheng
1The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China.
Abstract:
The mTOR pathway is a central control of cell growth, proliferation, metabolism, and survival, and is deregulated in most cancers. Cancer cells are addicted to increased activity of mTOR kinase-mediated signaling pathways, leading to numerous inhibitors of mTOR signaling in preclinic and clinical trials for cancer therapy. Phosphorus-containing sirolimus (FIM-A), which targets mTOR signaling, inhibits cancer cell growth in vitro. Here we report that FIM-A reduces the angiogenesis and proliferation of osteosarcoma both in vitro and in vivo. In cultured osteosarcoma cell lines, FIM-A inhibited cell proliferation and arrested cells in the G1 phase of the cell cycle, accompanied with reduction of VEGF and HIF-1alpha. With in vivo mouse osteosarcoma xenografts, FIM-A treatment resulted in the inhibition of mTORC1 signaling as demonstrated by the decreased phosphorylation of p70S6K1 and 4E-BP1. Consistent with this finding, FIM-A significantly decreased the average tumor volume, nuclei staining of PCNA, and the number of intratumoral microvessels. Our data demonstrated that targeting mTORC1 by FIM-A inhibited the growth of osteosarcoma in vitro and in vivo, providing the basis for further development of FIM-A as a therapy for osteosarcoma patients.
Insights
Phosphorus-containing sirolimus (FIM-A) effectively inhibits osteosarcoma growth by targeting the mTOR pathway. This novel agent reduces tumor proliferation, angiogenesis, and key signaling molecules, showing promise for osteosarcoma therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The mechanistic target of rapamycin (mTOR) pathway is crucial for cell growth and survival, and its dysregulation is common in cancers.
- Cancer cells often exhibit heightened dependence on mTOR signaling, driving the development of mTOR inhibitors for therapeutic strategies.
- Osteosarcoma, a primary bone cancer, presents a significant unmet need for effective treatments.
Purpose of the Study:
- To investigate the efficacy of phosphorus-containing sirolimus (FIM-A), an mTOR signaling inhibitor, against osteosarcoma.
- To evaluate the effects of FIM-A on osteosarcoma cell proliferation, angiogenesis, and relevant molecular pathways in vitro and in vivo.
Main Methods:
- In vitro studies involved treating cultured osteosarcoma cell lines with FIM-A to assess cell proliferation, cell cycle progression, and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1alpha).
- In vivo studies utilized mouse osteosarcoma xenograft models to evaluate FIM-A's impact on mTORC1 signaling (assessed by p70S6K1 and 4E-BP1 phosphorylation), tumor volume, proliferation marker (PCNA), and microvessel density.
Main Results:
- FIM-A significantly inhibited osteosarcoma cell proliferation and induced G1 cell cycle arrest in vitro, accompanied by reduced VEGF and HIF-1alpha levels.
- In vivo, FIM-A treatment suppressed mTORC1 signaling, decreased tumor volume, reduced PCNA-positive cells, and diminished intratumoral microvessel counts.
- FIM-A demonstrated anti-angiogenic and anti-proliferative effects on osteosarcoma in both experimental settings.
Conclusions:
- Targeting the mTORC1 pathway with FIM-A effectively inhibits osteosarcoma growth both in vitro and in vivo.
- FIM-A exhibits anti-angiogenic and anti-proliferative properties, making it a potential therapeutic candidate for osteosarcoma.
- These findings support the further clinical development of FIM-A for treating osteosarcoma patients.
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