Improvement of the performance of anticancer peptides using a drug repositioning pipeline. Issue 1 (14th November 2021) - Mohammadi, Elyas
Abstract: The use of anticancer peptides (ACPs) as an alternative/complementary strategy to conventional chemotherapy treatments has been shown to decrease drug resistance and/or severe side effects. However, the efficacy of the positively‐charged ACP is inhibited by elevated levels of negatively‐charged cell‐surface components which trap the peptides and prevent their contact with the cell membrane. Consequently, this decreases ACP‐mediated membrane pore formation and cell lysis. Negatively‐charged heparan sulphate (HS) and chondroitin sulphate (CS) have been shown to inhibit the cytotoxic effect of ACPs. In this study, we propose a strategy to promote the broad utilization of ACPs. In this context, we developed a drug repositioning pipeline to analyse transcriptomics data generated for four different cancer cell lines (A549, HEPG2, HT29, and MCF7) treated with hundreds of drugs in the LINCS L1000 project. Based on previous studies identifying genes modulating levels of the glycosaminoglycans (GAGs) HS and CS at the cell surface, our analysis aimed at identifying drugs inhibiting genes correlated with high HS and CS levels. As a result, we identified six chemicals as likely repositionable drugs with the potential to enhance the performance of ACPs. The codes in R and Python programming languages are publicly available in https://github.com/ElyasMo/ACPs_HS_HSPGs_CS . As a conclusion, these six drugs are highlighted as excellent targets for synergistic studies with ACPs aimed at lowering the costs associated with ACP‐treatment. Graphical Abstract and Lay Summary: Positively‐charged anticancer peptides (ACPs) have been proposed as potential alternatives to conventional chemotherapy treatments. However, Heparan Sulphate (HS) and Chondroitin Sulphate (CS), as negatively‐charged cell‐surface components, are considered as obstacles in the way of ACPs performance. Accordingly, we developed a drug repositioning pipeline to analyse the transcriptomic profiles, provided by LINCS L1000 projects, in order to discover the drugs that can diminish the level of HS and CS at the cell surface of cancer cells. As a result, six drugs were proposed as candidates to be used in synergistic studies with ACPs.