Affiliation:
1. Department of Applied Biology and Chemical Technology and Central Laboratory of the Institute of Molecular Technology for Drug
Discovery and Synthesis, The Hong Kong Polytechnic University, Hong
Kong, People's Republic of
China
2. State Key Laboratory in Chinese Medicine and Molecular
Pharmacology, Shenzhen, People's Republic of
China
3. Department of
Chemistry, University of Hong Kong, Hong Kong, People's Republic of
China
Abstract
ABSTRACT
Drug
resistance by overexpression of ATP-binding cassette (ABC) transporters
is an impediment in the treatment of leishmaniasis. Flavonoids are
known to reverse multidrug resistance (MDR) in
Leishmania
and
mammalian cancers by inhibiting ABC transporters. Here, we found that
synthetic flavonoid dimers with three (compound 9c) or four
(compound 9d) ethylene glycol units exhibited a significantly higher
reversing activity than other shorter or longer ethylene glycol-ligated
dimers, with ∼3-fold sensitization of pentamidine and sodium
stibogluconate (SSG) resistance in
Leishmania
, respectively.
This modulatory effect was dosage dependent and not observed in
apigenin monomers with the linker, suggesting that the modulatory
effect is due to its bivalent nature. The mechanism of reversal
activity was due to increased intracellular accumulation of pentamidine
and total antimony in
Leishmania
. Compared to other MDR
modulators such as verapamil, reserpine, quinine, quinacrine, and
quinidine, compounds 9c and 9d were the only agents that can reverse
SSG resistance. In terms of reversing pentamidine resistance, 9c and 9d
have activities comparable to those of reserpine and quinacrine.
Modulators 9c and 9d exhibited reversal activity on pentamidine
resistance among
LeMDR1
−/−
,
LeMDR1
+/+
, and
LeMDR1
-overexpressed mutants, suggesting that these modulators
are specific to a non-LeMDR1 pentamidine transporter. The
LeMDR1
copy number is inversely related to pentamidine
resistance, suggesting that it might be involved in importing
pentamidine into the mitochondria. In summary, bivalency could be a
useful strategy for the development of more potent ABC transporter
modulators and flavonoid dimers represent a promising reversal agent
for overcoming pentamidine and SSG resistance in parasite
Leishmania
.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
43 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献