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.
The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
Sonia
S
Arora
Jin-Ming
JM
Yang
Ryutaro
R
Utsumi
Tadashi
T
Okamoto
Takashi
T
Kitayama
William N
WN
Hait
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