ORCID Profile
0000-0002-1156-3410
Current Organisation
The University of Edinburgh
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Publisher: Cold Spring Harbor Laboratory
Date: 28-10-2022
DOI: 10.1101/2022.10.27.513961
Abstract: Acquired drug-resistance is a recurring problem in cancer treatment, and this is particularly true for patients with metastatic melanoma that carry a BRAF V600E mutation. In the current study, we explored the use of membrane-active peptides as an alternative therapeutic modality to target drug-resistant melanoma cells. We produced slow-cycling and drug-resistant melanoma cells using dabrafenib, a small molecule drug that targets tumor cells with BRAF V600E mutation, and characterised their lipidome and proteome to investigate the role of membrane lipids in acquired drug-resistance. Despite some changes in the lipid composition, tested anti-melanoma membrane-active cyclic peptides (cTI and cGm) killed melanoma cells that are sensitive, tolerant, or resistant to dabrafenib. Importantly, melanoma cells did not develop resistance to cTI or cGm, nor changed their lipid composition with long-term peptide treatment. Therefore, these peptides are well suited as templates to design therapeutic leads to target drug-resistant metastatic melanoma cells and/or as co-treatment with small molecule drugs.
Publisher: Springer Science and Business Media LLC
Date: 27-11-2022
DOI: 10.1007/S00018-022-04633-3
Abstract: Lactate dehydrogenase 5 (LDH5) is overexpressed in many cancers and is a potential target for anticancer therapy due to its role in aerobic glycolysis. Small-molecule drugs have been developed as competitive inhibitors to bind substrate/cofactor sites of LDH5, but none reached the clinic to date. Recently, we designed the first LDH5 non-competitive inhibitor, cGmC9, a peptide that inhibits protein-protein interactions required for LDH5 enzymatic activity. Peptides are gaining a large interest as anticancer agents to modulate intracellular protein-protein interactions not targetable by small molecules however, delivery of these peptides to the cytosol, where LDH5 and other anticancer targets are located, remains a challenge for this class of therapeutics. In this study, we focused on the cellular internalisation of cGmC9 to achieve LDH5 inhibition in the cytosol. We designed cGmC9 analogues and compared them for LDH5 inhibition, cellular uptake, toxicity, and antiproliferation against a panel of cancer cell lines. The lead analogue, [R/r]cGmC9, specifically impairs proliferation of cancer cell lines with high glycolytic profiles. Proteomics analysis showed expected metabolic changes in response to decreased glycolysis. This is the first report of a peptide-based LDH5 inhibitor able to modulate cancer metabolism and kill cancer cells that are glycolytic. The current study demonstrates the potential of using peptides as inhibitors of intracellular protein-protein interactions relevant for cancer pathways and shows that active peptides can be rationally designed to improve their cell permeation.
Publisher: American Chemical Society (ACS)
Date: 25-03-2021
Publisher: Wiley
Date: 07-05-2020
DOI: 10.1002/PEP2.24168
Location: United Kingdom of Great Britain and Northern Ireland
Location: Belgium
No related grants have been discovered for Ferran Nadal-Bufí.