Human cells need structures called mitochondria to generate energy for their biochemical activities – and cancer cells are no exception. Researchers at the Karolinska Institute in Sweden have concluded that breaking these small power stations could be a strategy for treating cancer.
Following that idea, the scientists designed oral inhibitors that could target mitochondrial DNA (mtDNA). In mice, treatment with the drug resulted in strong anti-tumor responses, slowing tumor growth without affecting healthy cells, the team reported in Nature.
The data support further development of the drug as a first-class mitochondria inhibitor for potential cancer treatment, the researchers said in the paper.
Cancer cells need mitochondria not only for energy but also to produce a number of building blocks to support their wild growth.
Previous attempts to target mitochondria for cancer treatment often led to adverse effects because mitochondria are also important for maintaining normal cell functions.
The Karolinska-led team focused on a specific feature of cancer cells. As part of unregulated cell division, cancer cells need to regenerate new mitochondria. So, instead of focusing directly on existing mitochondria, the team went after mitochondrial DNA transcription, which is essential for new mitochondria formation and energy production.
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“Previous findings from our research group have shown that rapid division of cells, such as cancer cells, is highly dependent on mtDNA to create new functioning mitochondria,” explained Nils-Göran Larsson, lead author of the study, in the recitation.
The team tested a small-molecule inhibitor of mitochondrial transcription in different cancer cell lines and recorded a strong reduction in cell viability in about one-third of them. The drug was not toxic to human mononuclear blood cells – which are important for immune function – or to human liver cells.
Further analysis showed that there was a cellular energy crisis. The treatment significantly reduced the production of ATP, which carries energy in cells. It also reduced nutrition, leading to the loss of some essential cell building blocks.
Inspired by the in vitro results, the researchers tested a similar drug in mouse models of ovarian and colorectal cancer. There was a clear reduction in the amount of tumor in treated animals, the team said. In addition, there were no signs of liver or kidney toxicity, anemia or other side effects after four weeks of treatment once a day.
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Mitochondria has offered insights into cancer treatment for other research groups. A collaboration between Mount Sinai School of Medicine and IBM found that cells with fewer mitochondria were more likely to respond to drugs that induce programmed cell death.
Research by the University of Sheffield identified an enzyme called TDP1, which – in the release of a protein called TOP1 – helps repair mtDNA, suggesting that it may cause disruption has the process of selectively killing cancer cells.
Larsson and colleagues believe their findings suggest that targeting mtDNA may be a viable cancer treatment strategy. “We are excited to show that this new principle for cancer treatment works in animal models and we hope that the defenders will now take further steps to treat cancer in humans. , ”He said.