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A Comparative Approach to Characterize the Landscape of Host-Pathogen Protein-Protein Interactions
Published on: July 18, 2013
P-glycoprotein mediates resistance to histidine kinase inhibitors
Sonia Arora1, Jin-Ming Yang, Ryutaro Utsumi
1The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
Abstract:
Histidine kinase inhibitors are being developed as a new class of antimicrobial drugs. We recently demonstrated the activity of a class of histidine kinase inhibitors against a mammalian enzyme, elongation factor-2 kinase (eEF-2K), and the effect of these compounds on cancer cell viability (Arora et al., 2003). To further characterize these compounds, we studied their interaction with ATP-binding cassette transporters, which are known to mediate resistance to a variety of chemotherapeutic agents. The 24 compounds studied belong to three structural series of derivatives of 2-methylimidazolium iodide. We focused this work on a representative compound (NH125) because we found it to be most potent against both histidine kinase and eEF-2K among the series. Cell lines that expressed P-glycoprotein (P-gp) were 2- to 5-fold resistant to NH125. NH125 increased accumulation of P-gp substrates such as paclitaxel and doxorubicin but had no effect on the accumulation of non-P-gp substrates. P-gp modulators verapamil and trans-flupenthixol and MDR1-targeted siRNA increased sensitivity of multidrug-resistant cell lines to NH125. The presence of a benzyl group on the N-3 position of the 2-methylimidazolium iodide was important for the interaction with P-gp. C6-NH, an NH125-resistant cell line, markedly overexpressed P-gp compared with the parental cell line. In animal models, we found that NH125 increased by 129% the survival of sensitive P388 cells bearing mice but had no effect on mice harboring the resistant cell line. These observations indicate that certain histidine kinase inhibitors are substrates for P-gp and hence an important consideration in development of these agents as potential antimicrobial and anticancer agents.
Insights
Histidine kinase inhibitors show anticancer and antimicrobial potential. However, P-glycoprotein (P-gp) can cause resistance by transporting these drugs, impacting their therapeutic development.
Area of Science:
- Biochemistry
- Pharmacology
- Cancer Research
Background:
- Histidine kinase inhibitors are a novel class of antimicrobial drug candidates.
- Previous studies demonstrated their activity against mammalian elongation factor-2 kinase (eEF-2K) and cancer cell viability.
- ATP-binding cassette transporters, particularly P-glycoprotein (P-gp), are implicated in multidrug resistance.
Purpose of the Study:
- To investigate the interaction of histidine kinase inhibitors with ATP-binding cassette transporters.
- To characterize the role of P-glycoprotein in resistance to these novel compounds.
- To evaluate the potential of these inhibitors as antimicrobial and anticancer agents considering drug transporter interactions.
Main Methods:
- Tested 24 derivatives of 2-methylimidazolium iodide, focusing on NH125.
- Utilized cell lines expressing P-glycoprotein (P-gp) to assess resistance.
- Examined the effect of NH125 on the accumulation of known P-gp substrates.
- Investigated the impact of P-gp modulators and MDR1-targeted siRNA on drug sensitivity.
- Analyzed the role of a benzyl group in P-gp interaction.
- Assessed drug efficacy in animal models with sensitive and resistant cell lines.
Main Results:
- Cell lines expressing P-gp exhibited 2- to 5-fold resistance to NH125.
- NH125 increased the accumulation of P-gp substrates like paclitaxel and doxorubicin.
- P-gp modulators and siRNA enhanced sensitivity of resistant cell lines to NH125.
- A benzyl group on the N-3 position of 2-methylimidazolium iodide was crucial for P-gp interaction.
- NH125 significantly improved survival in animal models with sensitive cells but not resistant cells.
Conclusions:
- Certain histidine kinase inhibitors, like NH125, are substrates for P-glycoprotein.
- P-gp mediated resistance significantly impacts the efficacy of these compounds.
- Understanding P-gp interactions is critical for developing histidine kinase inhibitors as antimicrobial and anticancer therapies.
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