Inhibition of Mitochondrial DNA Transcription as an Approach to Universal Cancer Therapy

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The key to a universal cancer therapy is to find a vulnerability that is (a) common to all cancers, something fundamental to cancer as a class, (b) nowhere near as prevalent in normal cells, and (c) can be cost-effectively exploited as a basis for treatment. Lengthening of telomeres is a good example, and an area in which at least a few groups are working at an early stage. Cancer cells must employ telomerase or alternative lengthening of telomeres mechanisms to evade the Hayflick limit on replication, triggered by short telomeres, as telomere length is reduced with each cell division. Other examples include other mechanisms related to cell replication, unsurprisingly given that unfettered replication is a defining characteristic of cancer. Today's research materials discuss an interesting example of this type of approach.

Researchers here note that production of proteins from mitochondrial DNA is critical to cell replication. Yet their experiments in interfering in that process demonstrate that mitochondrial gene expression is not so critical that it can't be turned off for a while in normal tissues, given a normal rate of cell division. Cancerous cells, on the other hand, with their rampant pace of replication, run into issues if their ability to produce proteins from mitochondrial DNA is impaired. Reducing the ability of cancerous cells to replicate is a promising way to improve the effectiveness of any treatment based on killing cancerous cells, and particularly if it can be applied to any cancer by virtue of the universality of the underlying mechanism.

Novel principle for cancer treatment shows promising effect

Mitochondria are the power plants of our cells. They are essential for converting the energy in the food we eat into the common energy currency that is required for a variety of cellular functions. Cancer cells are critically dependent on mitochondria, not only for providing energy but also for producing a variety of building blocks needed to make more cells as the cancer cells divide. The continuous cell division means that a cancer cell must constantly make new mitochondria in order to grow.

Previous attempts to target mitochondria for cancer treatment have focused on acutely inhibiting mitochondrial function. However, this strategy has often resulted in severe side effects due to the crucial role of mitochondria for normal tissue function. As an alternative, researchers developed a novel strategy that does not directly interfere with the function of existing mitochondria. Instead, they designed highly selective inhibitors that target the mitochondria's own genetic material, mtDNA, which has a critical role in the formation of new mitochondria.

When investigating the mechanism of action of these novel inhibitors, the researchers observed that the inhibitors put cancer cells into a state of severe energy and nutrient depletion. This leads to loss of necessary cellular building blocks, reduced tumour cell growth and ultimately cell death. "Previous findings from our research group have shown that rapidly dividing cells, such as cancer cells, are crucially dependent on mtDNA to form new functional mitochondria. Consequently, treatment with our inhibitors specifically affects proliferation of tumour cells, whereas healthy cells in tissues such as skeletal muscle, liver, or heart remain unaffected for a surprisingly long time."

Small-molecule inhibitors of human mitochondrial DNA transcription

Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration, and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system. The IMTs efficiently impair mtDNA transcription and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines.

The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease.

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source https://www.fightaging.org/archives/2020/12/inhibition-of-mitochondrial-dna-transcription-as-an-approach-to-universal-cancer-therapy/