P-glycoprotein mediates resistance to histidine kinase inhibitors.
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.
Arora
Sonia
S
The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
Yang
Jin-Ming
JM
Utsumi
Ryutaro
R
Okamoto
Tadashi
T
Kitayama
Takashi
T
Hait
William N
WN
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000071677:Histidine Kinase; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; C414024:NH 125; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011494:Protein Kinases; D000071677:Histidine Kinase; D017239:Paclitaxel