Could the latest development of
catalytic topoisomerase II inhibitors be saving grace?
Have they finally found a possible solution to
decreasing the potential side effects of toxicity, both cardiac and renal, in
patients who are taking antibiotics or receiving chemotherapy drugs? In light
of our recent lectures regarding major health issues such as breast cancer and
antibiotic resistant bacteria, the latest development of anticancer drug
topoisomerase inhibitors has pretty much hit home for those who have developing
or metastasized breast cancer but could this discovery be saving grace for
those suffering from bacteria resistant infections?
N. gonorrhoeae bacterium has been around forever
now and over time has continued to find comfort in their environment becoming
more and more resistant to antibiotic use. With this new development, I
question whether or not one of the more recent “retired” drugs, Fluroquinolone
could still be effective had it had the same mechanism of action as the latest
topoisomerase II inhibitors. As we know it, normal type II topoisomerases
functions by nicking DNA and resealing. However, when using Fluroquinolone to
treat a gonorrhea infection, nicks cannot be resealed and the accumulation of
bacterial DNA from nicks causes DNA fragmentation and cell death. One could develop
severe side effects due to the toxicity of these fragments.
On the same
note, anticancer drugs cause cardiac and renal toxicity leading to major health
issues or even death. Most anticancer drugs use a traditional mechanism by
directly inhibiting topoisomerase activity; blocking the ligation of the
cleaved DNA. However, there is a growing class of anticancer agents that causes
DNA cleavage blockage and re-ligation but by a noncompetitive mechanism rather than directly targeting the topoisomerase receptors
for re-ligation. HU-331 has been identified as a potential anticancer
drug that has higher potency in cancer cells with less off-target toxicity than
other anticancer drugs. HU-331 has also been reported to decrease the ability
of topoisomerase II to bind DNA and inhibit ligation without the presence of
DNA cleavage poison. Although the exact mechanism is still a mystery and much
to be known about HU-331, it has been shown that noncompetitive binding of the
topoisomerase inhibitors is a promising foundation for the future of anticancer
drugs and antibiotics which could be a possible
breakthrough for finding a solution to extending the efficacy of antibiotics.
With this discovery of HU-331 and consideration of similarities
in mechanism in regards to topoisomerase activity, could drugs like HU-331 aid
in the development of a drug that can prevent bacteria from becoming resistant
in most infections or could it extend its period of efficacy?
Regal,
Kellie M. HU-331 Is a Catalytic Inhibitor of Topoisomerase IIα
Chemical Research in Toxicology
2014 27 (12), 2044-2051
DOI: 10.1021/tx500245m
