Improved Anti-Tumor Activity of Novel Highly Bioactive Liposome-Bound TRAIL in Breast Cancer Cells
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Published on: November 1, 2017
Diego De Miguel, Ana Gallego-Lleyda, José M Ayuso
1Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/ Pedro Cerbuna 12, Zaragoza, 50009 Spain. lumartin@unizar.es.
Background:
Apo2-ligand/TRAIL, a member of the TNF cytokine superfamily capable of inducing apoptosis on tumor cells while sparing normal cells, is a promising anti-tumor agent. However, about 50% of human cancer are TRAIL resistant. Consequently, future TRAIL-based therapies will require the use of novel highly bioactive forms of TRAIL and/or the addition of sensitizing agents to TRAIL-induced apoptosis. Recently, we demonstrated that artificial lipid nanoparticles coated with bioactive TRAIL (LUV-TRAIL) greatly improved TRAIL activity and were able to induce apoptosis in chemoresistant hematological tumor cells.
Objective:
In this study, we have tested LUV-TRAIL-pro-apoptotic potential in human breast cancer.
Method:
Comparative analysis of cytotoxicity induced by sTRAIL and LUV-TRAIL was performed using several human breast tumor cell lines with different sensitivity to TRAIL. In vivo anti-tumor activity of LUV-TRAIL was also studied using a xeno-graft tumor model.
Results:
LUV-TRAIL improved not only sTRAIL in vitro cytotoxicity in all breast tumor cell lines tested but also showed more anti-tumor activity than sTRAIL in an in vivo xeno-graft tumor model. On the other hand, the concomitant treatment of LUV-TRAIL with the sensitizing agent flavopiridol (FVP) induced a higher level of cell death in TRAIL-resistant cell lines. TRAIL-sensitization induced by FVP was mediated by DR5 up-regulation, and interestingly TRAIL-apoptotic signaling was completely shifted towards DR5 upon FVP treatment. LUV-TRAIL could especially take advantage of this DR5 up-regulation, while sTRAIL was not able.
Conclusion:
To date, no special attention had been paid to this aspect of FVP-induced TRAIL-sensitization, may be because sTRAIL used were not able to take advantage of this DR5 up-regulation. Hence, LUV-TRAIL could be a better choice than sTRAIL to be used in combination with anti-tumor drugs inducing DR5 over-expression, since LUV-TRAIL is especially effective activating this death-receptor.
Insights
Lipid nanoparticle-based TRAIL (LUV-TRAIL) enhances anti-tumor activity in breast cancer models. LUV-TRAIL combined with flavopiridol effectively overcomes TRAIL resistance by upregulating DR5 expression.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Apo2-ligand/TRAIL is a promising anti-tumor agent but faces resistance in ~50% of human cancers.
- Novel TRAIL formulations and sensitizing agents are crucial for effective TRAIL-based therapies.
- Lipid nanoparticle-conjugated TRAIL (LUV-TRAIL) demonstrated enhanced apoptosis in chemoresistant hematological tumors.
Purpose of the Study:
- To evaluate the pro-apoptotic potential of LUV-TRAIL in human breast cancer.
- To compare the efficacy of LUV-TRAIL with soluble TRAIL (sTRAIL) in breast cancer models.
- To investigate the synergistic effects of LUV-TRAIL with sensitizing agents like flavopiridol (FVP).
Main Methods:
- Comparative in vitro cytotoxicity assays using various human breast tumor cell lines.
- In vivo anti-tumor activity assessment using a xenograft tumor model.
- Analysis of TRAIL-sensitization mechanisms, including DR5 up-regulation.
Main Results:
- LUV-TRAIL exhibited superior in vitro cytotoxicity and in vivo anti-tumor activity compared to sTRAIL.
- Concomitant treatment with LUV-TRAIL and FVP significantly increased cell death in TRAIL-resistant cell lines.
- FVP-induced TRAIL sensitization was mediated by DR5 up-regulation, which LUV-TRAIL effectively utilized.
Conclusions:
- LUV-TRAIL demonstrates enhanced efficacy over sTRAIL in breast cancer treatment.
- LUV-TRAIL combined with FVP offers a potent strategy to overcome TRAIL resistance.
- LUV-TRAIL is a promising therapeutic candidate for combination therapy with DR5-overexpressing drugs.
