Improvement of the performance of anticancer peptides using a drug repositioning pipeline

Area of Science:

• Biochemistry
• Pharmacology
• Genomics

Background:

• Anticancer peptides (ACPs) offer an alternative to chemotherapy, potentially reducing side effects and drug resistance.
• Positively-charged ACPs efficacy is limited by negatively-charged cell surface components like heparan sulphate (HS) and chondroitin sulphate (CS), which impede peptide-cell membrane interaction.
• This interaction is crucial for ACP-mediated membrane pore formation and subsequent cell lysis.

Purpose of the Study:

• To develop a drug repositioning strategy to identify compounds that can enhance anticancer peptide (ACP) efficacy.
• To overcome the inhibitory effects of negatively-charged glycosaminoglycans (GAGs) on the cell surface, thereby promoting broader ACP utilization.
• To identify drugs that downregulate the expression of genes associated with high levels of HS and CS.

Main Methods:

• Utilized a drug repositioning pipeline analyzing transcriptomics data from the LINCS L1000 project.
• Examined four cancer cell lines (A549, HEPG2, HT29, MCF7) treated with numerous drugs.
• Focused on identifying drugs that inhibit genes known to modulate cell surface HS and CS levels.

Main Results:

• Identified six chemical compounds as potential repositionable drugs capable of enhancing ACP performance.
• The analysis correlated drug treatments with changes in GAG-associated gene expression.
• Computational resources, including R and Python code, are publicly available for reproducibility.

Conclusions:

• The six identified drugs are promising candidates for synergistic studies with ACPs.
• This approach could lead to more cost-effective cancer treatments by improving ACP efficacy.
• Further research is warranted to validate the synergistic potential of these drug-ACP combinations.