A new anti-cancer drug prevents cancer by targeting the cancer “power plants”.

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Inhibiting the expression of genes within mitochondria in mice prevents cancer cells from developing.

A newly discovered active ingredient has the potential to stop cancer cells from reproducing by killing their “power plants”

The chemical in the new agent prevents genetic information from being read in the mitochondria. Researchers at the Max Planck Institute for Biology of Aging in Cologne, the Karolinska Institute in Stockholm and the University of Gothenburg have discovered that this active ingredient is capable of shielding mice from tumors; the same findings were observed in human patients.

Mitochondria provide energy for our cells, and the building blocks required to support healthy tissue and organ function.

For many years, it was claimed that the growth of cancer cells did not rely on normal cell function. This well-established philosophy hasn’t been embraced in recent years.

To a great extent, cancer stem cells rely on mitochondrial metabolism for survival.

Since cancer cells depend so heavily on mitochondria for normal cellular function, targeting mitochondria in cancer therapy has proven to be quite difficult.

Now, a worldwide team has found a solution to the common problem. “We have succeeded in establishing a potential cancer drug that targets mitochondrial function without severe side effects and without harming healthy cells,” explains Nina Bonekamp. Mitochondria have their own personal collection of genes, mitochondrial DNA, which is influenced by the cellular proteins.

One of the subsections of this paper is titled “mitochondrial RNA polymerase,” Our previous studies have shown that rapidly proliferating cells are particularly sensitive to the inhibition of mitochondrial expression, whereas differentiated tissues can tolerate this state for a remarkably long time.

We decided that POLRMT, as a key regulator of mtDNA expression, could be considered a promising target.

Compound interferes with RNA polymerase.
In connection with the lead discovery center, a translational drug discovery organization created by Max Planck, we developed an assay method to classify a chemical compound that inhibits POLRMT.

The POLRMT inhibitor altered the development of cancer cells, but it was well tolerated in mice.

“Our results indicate that by starving cancer cells to death, we are theoretically limiting their development without significant toxic side effects for at least a period of time.

This will turn out to be an unprecedented opportunity for us to treat cancer. Another benefit of our inhibitor is that we know where it binds, what it does to POLRMT and exactly how it inhibits the protein.

In comparison to most medications being used in clinical trials.”.

With the aid of ACUS Laboratories and Max Planck Institute, the team was able to isolate the POLRMT inhibitor, and then made the structural determination of the inhibitor complex.

Bonekamp and Larsson accept that the transformation of basic results into a potential drug was a challenging and exciting undertaking.

They are infinitely enthusiastic about the new perspectives they have gleaned.

“Given the central role of mitochondrial metabolism in the cell, I am confident that our inhibitor of mitochondrial gene expression can be used as a tool in a variety of areas,” Bonekamp says. “Of course, it’s fascinating to further pursue its potential as an anticancer drug, but also as a model compound to better understand the cellular effects of mitochondrial dysfunction and mitochondrial diseases.”.

Reference: “Small-molecule inhibitors of human mitochondrial DNA transcription”

Bonekamp, P. B., Hillen, S., Felser, A., Bergbrede, T., Choidas, A., Horn, M., Unger, A., Di Lucrezia, I., Atanassov, I., Li, X., Koch, U., Menninger, S., Boros, J., Giavalisco, P., Habenberger, P. C., Cramer, P.

Denzel, Peter Nussbaumer, Bert Klebl, Maria Falkenberg, Claes M. Gustafsson, and Nils-Göran Larsson, Dec 16, 2020, Nature.DOI: 10.1038/s41586-020-03048-z.

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