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: Jasna Banković, Jörg Andrä, Nataša Todorović, Ana Podolski-Renić, Zorica Milošević, Dorđe Miljković, Jannike Krause, Sabera Ruždijić, Nikola Tanić, Milica Pešić
• Journal: Experimental cell research (Exp Cell Res) Vol. 319 Issue 7 Pg. 1013-27 (Apr 15 2013) ISSN: 1090-2422 [Electronic] United States
• PMID: 23298945 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antimicrobial Cationic Peptides
• Antineoplastic Agents
• NK-lysin
• Peptides
• Proteolipids
• peptide NK-2

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Antimicrobial Cationic Peptides (pharmacology)
• Antineoplastic Agents (pharmacology)
• Biological Transport (drug effects)
• Cell Line, Tumor
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Peptides (pharmacology)
• Proteolipids (metabolism)