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Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions
Published on: December 20, 2017
Dpep, a Cell-Penetrating Peptide Targeting ATF5, CEBPB and CEBPD, Synergistically Combines with ABT-263 and
Qing Zhou1, Trang Thi Thu Nguyen1,2, James M Angelastro3
1Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.
Abstract:
Dpep is a cell-penetrating peptide that targets transcription factors ATF5, CEBPB and CEBPD to selectively suppress growth and survival of diverse tumor cell types in vitro and in vivo. Due to these actions and its apparent safety, the peptide has potential as a cancer therapeutic. How Dpep might be combined with other anti-cancer agents to achieve synergistic efficacy and to overcome possible peptide resistance has not been assessed in depth. Based on prior work indicating that Dpep promotes apoptotic cancer cell death and up-regulates multiple pro-apoptotic and tumor suppressor genes, we studied combinations of Dpep with ABT-263, a pro-apoptotic BCL2 family inhibitor, and decitabine, a hypomethylating drug. Combining Dpep with each agent alone or together synergistically suppressed the growth of a range of solid and liquid tumor cell types. Moreover, the combinations synergistically inhibited the growth of cells lines that were selected either in vivo or in vitro for Dpep resistance. Finally, we tested the combination of Dpep with ABT-263 in a mouse melanoma xenograft model. The combination more effectively inhibited tumor growth than either agent alone and, in contrast to vehicle or ABT-263, produced a 40% durable survival rate. Taken together, these observations highlight potential drug partners for the therapeutic development of Dpep.
Insights
The cell-penetrating peptide Dpep, combined with ABT-263 or decitabine, synergistically inhibits diverse cancer cell growth, even overcoming Dpep resistance. Combinations demonstrate significant therapeutic potential in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Dpep is a cell-penetrating peptide targeting transcription factors ATF5, CEBPB, and CEBPD, showing selective tumor cell suppression and potential as a cancer therapeutic.
- Investigating Dpep combinations is crucial for enhancing efficacy and overcoming potential peptide resistance in cancer treatment.
Purpose of the Study:
- To assess the synergistic efficacy of Dpep in combination with ABT-263 (BCL2 inhibitor) and decitabine (hypomethylating agent).
- To evaluate the effectiveness of these combinations against Dpep-resistant cancer cell lines.
- To determine the therapeutic potential of Dpep combinations in vivo using a melanoma xenograft model.
Main Methods:
- Combination studies of Dpep with ABT-263 and decitabine in various solid and liquid tumor cell types in vitro.
- Assessment of combination efficacy in Dpep-resistant cell lines selected in vitro and in vivo.
- In vivo efficacy testing of Dpep and ABT-263 combination in a mouse melanoma xenograft model.
Main Results:
- Dpep combined with ABT-263 or decitabine synergistically suppressed the growth of diverse tumor cell types.
- The combinations effectively inhibited Dpep-resistant cell lines, indicating a strategy to overcome resistance.
- In a mouse melanoma model, the Dpep and ABT-263 combination significantly inhibited tumor growth and achieved a 40% durable survival rate.
Conclusions:
- Dpep combinations with ABT-263 and decitabine show significant synergistic anti-cancer activity.
- These combinations hold promise for overcoming Dpep resistance and represent potential therapeutic strategies for various cancers.
- Further development of Dpep in combination therapies is warranted based on these preclinical findings.
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