Authors:
Henry A. Charlier, Jr.
Affiliation:
Title: Inhibition of Carbonyl Reductase as a Means to Improve Anthracycline Chemotherapy
Abstract: Carbonyl reductase (CR)
catalyzes the reduction of several carbonyl compounds, including the widely used
anthracycline anticancer drugs. CR
reduction of anthracyclines significantly impacts their use in the treatment of
cancer as it has been linked to both drug resistance and cardiotoxicity
mechanisms. Therefore, inhibition
of CR in conjunction with anthracycline therapy offers the potential both to
increase the effectiveness of the drugs in killing cancer cells and to decrease
the risk of the associated cardiotoxicity.
To date our lab has discovered several classes of novel inhibitors
ranging in KI values ranging from 0.1 - 70
mM.
These inhibitors are uncompetitive or noncompetitive inhibitors against
the carbonyl substrates. Of
particular interest are several biphenyl inhibitors.
These inhibitors are the most potent of the known CR inhibitors and
preliminary anthracycline cell killing studies in the presence of the CR
inhibitors increase anthracycline efficacy by four-fold.
Such findings demonstrate the potential for CR inhibitors to improve
anthracycline chemotherapy, however much more work is needed to better
understand the mechanism of action.
This research was supported by NIH/P20RR016454.