Nature: POLRMT variant inhibitors are effective against tumors and have no significant effect on healthy cells

Previous studies have targeted mitochondrial cancer treatment, focusing on acute inhibition of mitochondrial function.
because mitochondrials are also critical to the functioning of normal tissues, all of these treatment strategies often lead to serious side effects.
16th, in a new study by Nature, researchers at sweden's Karolinska Institute developed a new type of mitochondrial DNA (mtDNA) inhibitor to replace mitochondrial suppression methods that had previously been "lost and lost."
inhibitors prevent the proliferation of cancer cells and reduce tumor growth in mice, but do not have a significant effect on healthy cells.
: Nature Specifically, the researchers designed highly selective variant inhibitors IMT1 and IMT1B, an improved version of IMT1.
in-body experiments, both inhibitors significantly inhibited the catalytic activity of human mitochondrial RNA polymerase (POLRMT).
by altering the composition of pollRMT, affecting the binding and transcription of substrates, thereby impairing the expression of mtDNA and affecting the formation of new mitochondrials.
two non-competitive inhibitors, IMT1 and IMT1B (Source: Nature) IMT1 and IMT1B dose-dependent reduction of mitochondrial transcripts, resulting in mitochondrial depletion (Source: Nature) In order to test IMT For anti-tumor effects, the researchers treated heterogeneic transplant model mice with IMT1B orally for 4 weeks, mice showed good resistance to the drug, showed no signs of acute or chronic liver or renal toxicity, and inhibitors specifically affected the proliferation of tumor cells.
important is that healthy cells in tissues such as skeletal muscles, livers, or hearts remain unaffected for a considerable period of time.
IMT inhibits tumor growth and mitochondrial gene expression in the body in a dose-dependent manner (Source: Nature) When studying the mechanism of the new inhibitors, the researchers observed that cancer cells were severely consumed with energy and nutrients after using inhibitors.
the loss of essential cell composition, which leads to reduced tumor growth and eventually cell death.
IMT specifically inhibits the proliferation of cancer cells (Source: Nature) In addition, the researchers have observed that IMT can lead to the depletion of mtDNA in rapidly dividing HeLa cells, and previous genetic studies have shown that the splurged tissue can withstand the loss of mtDNA expression over a long period of time.
these results highlight the importance of mtDNA expression for rapidly dividing cells and explain why blocking mtDNA gene expression can have substantial anti-tumor effects without affecting normal tissue.
overall, the above results show that IMT is an effective and highly specific variant inhibitor targeting POLLMT, and the effective effect shown on cancer treatment in preclinical models will promote its development and application in human cancer.
" are promising, but further development is needed before they can be considered for human use.
the paper's author, Professor Nils-Göran Larsson, concluded.
: 1 s Bonekamp, N.A., Peter, B., Hillen, H.S. et al. Small-molecule inhibitors of human mitochondrial DNA transcription. Nature (2020) 2 s ny princip för cancer behandling visar lovande effekt (Source: Karolinska Institute, Sweden)