Fight ovarian cancer

In the search for new cancer drugs that are as side-effect free as possible, metal-containing compounds have taken center stage
.
In the journal Angewandte Chemie, a team of researchers describes how extremely low doses of rhenium metal complexes interfere with cellular metabolism to the point of killing ovarian cancer cells
.

Cisplatin was the first metal-containing antitumor drug, and others have been discovered since then
.
Recently, a new type of anti-tumor drug was discovered in TRIP, which is a special rhenium carbonyl complex.

TRIP causes proteins to aggregate rapidly, putting the endoplasmic reticulum (ER) – where protein synthesis, modification, and folding take place – in a state of tension, highly activating the unfolded protein reaction (UPR).

UPR is a cellular response
to the accumulation of large amounts of misfolded proteins in ER.
This leads to programmed cell death (apoptosis)
of tumor cells.

A team led by Samuel M.
Meier-Menches of the University of Vienna (Austria) and Justin J.
Wilson of Cornell University (Ithaca, NY/USA) used chemical proteomics to analyze the effects
of TRIP in more detail.
This method is used to identify cellular proteins
to which drugs bind.
Despite the wide toxicity of TRIP, the team was able to identify 89 independent, dose-dependent potential cellular target proteins in ovarian cancer cell lines — known as TRIP target proteins
.

In addition, the team used proteomic analysis to characterize
the response of live cancer cell lines to TRIP therapy.
This includes comparing the proteome, that is, all proteins in a cell, noting differences
in the concentration of individual proteins when adding and not adding different doses of the drug.

Taken together, these data suggest that the Fe-S cluster biogenesis factor NUBP2 may be the starting point
for TRIP-induced cellular processes.
Fe-S clusters are complexes
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 Fe-S cluster proteins.
TRIP treatment significantly reduced the amount of
Fe-S protein in ovarian cancer cells.
The amount of iron storage protein ferritin has increased
dramatically.
Bioenergetics of tumor cells confirm the deficiency
of Fe-S cluster proteins required for cellular respiration.

TRIP destroys the biogenesis of Fe-S clusters in ovarian cancer cells in very small doses so that they are generally non-cytotoxic
.
This makes it an interesting starting point for developing a selective anti-tumor drug that rarely has adverse side effects
.
This new combinatorial approach can be widely used in multi-pharmacology studies (effects on multiple targets)
of metal-based drug candidates.