Monday, November 28, 2016

Student post on treatment of cancer and bacteria resistant infections



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


5 comments:

  1. Very interesting how a different mechanism of action can help in preventing side effects caused by medications that have similar results from their mechanism of action. I think this brings up very optimistic future directions for creating treatment plans with less side effects to the patient.

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  2. I question this research on several levels, but mainly if it is going to be specifically used for the the renal and cardiac purposes. Don't get me wrong, the 're-use' and differences in mechanism of action is very promising. My questions come from: when would the doctor try to use it? Would it be economically feasible for the patient? Would it be used short term or long term? What would be the side effects (long term) or would this only be used in patients with a shorter mortality? Very enlightening though.

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  3. An interesting class of anticancer drugs, however, I'm wondering if this new mechanism will completely overwhelming renal and cardiac toxicity because I think even the other anticancer classes, not topoisomerase inhibitors, could cause these adverse effects. Good Job!

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  4. I think any drug that can possibly help with the bacterial resistance problem is worth looking into. However, there is no magic drug that will solve the resistance problem. Bacteria will eventually gain resistance to anything developed. Good job on this!

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  5. Great job on this! I think that this type of drug may be a great option in the future once more research and more studies are conducted.

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