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

• 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.

Ämnesord

NATURVETENSKAP  -- Biologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

Cell culture

Cell membranes

Chemotherapy

Drug interactions

Genes

Peptides

Pipelines

Sulfur compounds

Cell surfaces

Chemotherapy treatment

Chondroitinsulfate

Drug repositioning

Drug-resistance

Heparan sulphate

LINCS l1000

Negatively charged

Performance

Therapeutic peptides

Diseases

antineoplastic agent

chondroitin 4 sulfate

chondroitin sulfate

glycosaminoglycan

heparan sulfate

proteoheparan sulfate

peptide

A-549 cell line

antineoplastic activity

Article

breast adenocarcinoma

colorectal adenocarcinoma

controlled study

gene expression

gene expression profiling

gene interaction

gene ontology

gene regulatory network

Hep-G2 cell line

HT-29 cell line

human

human cell

liver cell carcinoma

MCF-7 cell line

non small cell lung cancer

transcriptomics

neoplasm

Antineoplastic Agents

Glycosaminoglycans

Humans

Neoplasms

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)