Rhenium tricarbonyl complex with antitumor activity targets Fe-S cluster biogenesis
Metal-containing complexes have taken up center stage in the search
for new cancer drugs that are as free of side effects as possible. In
the journal Angewandte Chemie, a research team has now described
how a very low dose of a rhenium metal complex interferes with cellular
metabolism to such an extent that it kills ovarian cancer cells.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
Cisplatin was the first metal-containing antitumor drug and others
have been discovered since. Recently, a new potential antitumor drug was
found in TRIP, a special rhenium carbonyl complex. TRIP causes rapid
protein aggregation, which puts the endoplasmic reticulum (ER)—where
protein synthesis, modification, and folding occur—under strain,
hyperactivating the unfolded protein response (UPR). UPR is a cellular
response to the accumulation of a large number of incorrectly folded
proteins in the ER. This results in the programmed cell death
(apoptosis) of tumor cells.
A team led by Samuel M. Meier-Menches at the University of Vienna
(Austria) and Justin J. Wilson at Cornell University (Ithaca, NY/USA)
has analyzed the effects of TRIP in more detail using chemoproteomics.
This method is used to identify which cellular proteins are bound by a
drug. Despite the broad toxic effects of TRIP, the team was able to
identify 89 individual, dose-dependent, potential cellular target
proteins in a line of ovarian cancer cells—this is called the target
landscape for TRIP.
In addition, the team characterized the response of the living cancer
cell line to treatment with TRIP by using proteome profiling. This
involves comparing the proteome, which is all the proteins of the cells,
with and without addition of various doses of the drug and noting
differences in the concentrations of individual proteins.
Taken together, these data point to the Fe-S cluster biogenesis
factor NUBP2 as the probable starting point for the cellular processes
triggered by TRIP. Fe-S clusters are complexes made of several iron and
sulfur atoms. As cofactors, they play an important role in many
enzymatic reactions, such as the respiratory chain. NUBP2 is essential
for the production of proteins with Fe-S clusters. Treatment with TRIP
significantly reduced the number of Fe-S proteins in ovarian cancer
cells. The quantity of the iron storage protein ferritin increased
drastically. The lack of Fe-S cluster proteins for cell respiration was
substantiated by the bioenergetics of the tumor cells.
TRIP disrupts the biogenesis of Fe-S clusters in ovarian cancer cells
in doses that are so small that they are not generally cytotoxic. This
makes it an interesting starting point for development of a selective
antitumor drug with few undesired side effects. This new combined
research method could be used broadly to study the polypharmacology
(effect on various targets) of metal-based drug candidates.
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About the Author
Dr. Samuel M. Meier-Menches is an Assistant Professor at the University of Vienna with
affiliations at the Faculty of Chemistry and the Joint Metabolome
Facility, a joint facility with the Medical University Vienna. He uses
post-genomic methods to uncover molecular mechanisms of drug action from
preclinical in vitro models to the analysis of patient samples.
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