title: The elimination of P-glycoprotein over-expressing cancer cells by antimicrobial cationic peptide NK-2: the unique way of multi-drug resistance modulation.
abstract: Most chemotherapeutics harm normal cells causing severe side effects and induce the development of resistance in cancer cells. Antimicrobial peptides (AMPs), recognized as anti-cancer agents, may overcome these limitations. The most studied mechanism underlying multi-drug resistance (MDR) is the over-expression of cell membrane transporter P-glycoprotein (P-gp), which extrudes a variety of hydrophobic drugs. Additionally, P-gp contributes to cell membrane composition and increases the net negative charge on cell surface. We postulated that NK-lysin derived cationic peptide NK-2 might discriminate and preferentially eliminate P-gp over-expressing cancer cells. To test this hypothesis, we employed MDR non-small cell lung carcinoma (NCI-H460/R) and colorectal carcinoma (DLD1-TxR) cell lines with high P-gp expression. MDR cancer cells that survived NK-2 treatment had decreased P-gp expression and were more susceptible to doxorubicin. We found that NK-2 more readily eliminated P-gp high-expressing cells. Acting in 'carpet-like' manner NK-2 co-localized with P-gp on the MDR cancer cell membrane. The inhibition of P-gp reduced the NK-2 effect in MDR cancer cells and, vice versa, NK-2 decreased P-gp transport activity. In conclusion, NK-2 could modulate MDR in unique way, eliminating the P-gp high-expressing cells from heterogeneous cancers and making them more vulnerable to classical drug treatment.
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia. jasnam@ibiss.bg.ac.rs
authors.forename: Jasna
authors.initials: J
authors.lastname: Banković
authors.forename: Jörg
authors.initials: J
authors.lastname: Andrä
authors.forename: Nataša
authors.initials: N
authors.lastname: Todorović
authors.forename: Ana
authors.initials: A
authors.lastname: Podolski-Renić
authors.forename: Zorica
authors.initials: Z
authors.lastname: Milošević
authors.forename: Dorđe
authors.initials: D
authors.lastname: Miljković
authors.forename: Jannike
authors.initials: J
authors.lastname: Krause
authors.forename: Sabera
authors.initials: S
authors.lastname: Ruždijić
authors.forename: Nikola
authors.initials: N
authors.lastname: Tanić
authors.forename: Milica
authors.initials: M
authors.lastname: Pešić
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D010455:Peptides / Q000494:pharmacology*; D011510:Proteolipids / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; C093238:NK-lysin; D010455:Peptides; D011510:Proteolipids; C475945:peptide NK-2