TY - JOUR
T1 - Improvement of the performance of anticancer peptides using a drug repositioning pipeline
AU - Mohammadi, Elyas
AU - Tahmoorespur, Mojtaba
AU - Benfeitas, Rui
AU - Altay, Ozlem
AU - Javadmanesh, Ali
AU - Lam, Simon
AU - Mardinoglu, Adil
AU - Sekhavati, Mohammad Hadi
N1 - Funding Information:
The authors acknowledge the entire staff of Systems Medicine group at the Science for Life Laboratory, KTH – Royal Institute of Technology. They also acknowledge support from Science for Life Laboratory, and Swedish National Infrastructure for Computing (SNIC) at UPPMAX for providing assistance in computational infrastructure.
Publisher Copyright:
© 2021 Wiley-VCH GmbH
PY - 2021/11/14
Y1 - 2021/11/14
N2 - 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.
AB - 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.
KW - cancer
KW - drug repositioning
KW - heparan sulfate
KW - LINCS L1000
KW - therapeutic peptides
UR - http://www.scopus.com/inward/record.url?scp=85119253169&partnerID=8YFLogxK
U2 - 10.1002/biot.202100417
DO - 10.1002/biot.202100417
M3 - Article
C2 - 34657375
AN - SCOPUS:85119253169
SN - 1860-6768
VL - 17
JO - Biotechnology Journal
JF - Biotechnology Journal
IS - 1
ER -
