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Improved Anti-Tumor Activity of Novel Highly Bioactive Liposome-Bound TRAIL in Breast Cancer Cells
- Source :
- Recent patents on anti-cancer drug discovery. 11(2)
- Publication Year :
- 2015
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Programmed cell death
Cell Survival
medicine.medical_treatment
Drug Compounding
Mice, Nude
Antineoplastic Agents
Breast Neoplasms
TNF-Related Apoptosis-Inducing Ligand
03 medical and health sciences
Mice
0302 clinical medicine
In vivo
Cell Line, Tumor
Drug Discovery
Medicine
Animals
Humans
Pharmacology (medical)
Cytotoxicity
business.industry
Cancer
General Medicine
medicine.disease
Xenograft Model Antitumor Assays
030104 developmental biology
Cytokine
Oncology
Apoptosis
Cell culture
030220 oncology & carcinogenesis
Immunology
Liposomes
Cancer research
Tumor necrosis factor alpha
Female
business
Subjects
Details
- ISSN :
- 22123970
- Volume :
- 11
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Recent patents on anti-cancer drug discovery
- Accession number :
- edsair.doi.dedup.....e74b730be0533012188600edfb8386d2