Asian Scientist Journal (Aug. 10, 2023) — To ease pains of chemotherapy for most cancers sufferers, researchers are all the time exploring higher choices. These are medication that both alleviate negative effects of chemotherapy or enhance its efficacy. Mannose, a sort of sugar discovered in lots of fruits, might provide a candy answer for the latter.
Lengthy earlier than scientists discovered mannose might kill most cancers cells, its toxicity was found elsewhere. In 1939, German scientist Theodor Staudenmayer discovered that feeding mannose to honeybees killed them. Later work revealed the trigger: honeybees lack mannose phosphate isomerase (MPI), an enzyme that converts mannose into fructose and again, as required. Consequently, they’ll’t course of mannose resulting in its build-up.
In a multi-institutional research revealed in eLife, researchers reveal a hyperlink between the anticancer exercise of mannose and its toxicity for honeybees.
Asian Scientist Journal spoke to Yoichiro Harada, a researcher at Osaka Worldwide Most cancers Institute and the lead writer of the research. “We discovered that the honeybee syndrome is a key mechanism behind how mannose enhances chemotherapy,” stated Harada.
To simulate the honeybee syndrome in human most cancers cells, the researchers deleted the gene that codes for MPI. When equipped with a focus of mannose near what’s naturally current in cells, the gene-edited most cancers cells thrived. After they have been starved of mannose, the cells didn’t proliferate as anticipated because of the function of mannose within the manufacturing of glycans, advanced sugars that dot the cell floor.
The most cancers cells additionally didn’t proliferate once they have been supplied with larger concentrations of mannose. Additional, these cells displayed higher vulnerability to chemotherapy brokers. Mannose hits a double punch: it makes most cancers cells develop extraordinarily slowly whereas opening their gates for cancer-treatment medication.
The staff investigated what makes this double punch doable. Wholesome cells undergo a cycle the place they double the quantity of DNA inside them earlier than dividing into two cells with equal quantities of DNA. Most cancers cells, in actual fact, undergo these cycles a lot quicker than wholesome cells that this extremely proliferative nature is a trademark of most cancers. The addition of mannose, nevertheless, stalled their proliferation. The researchers noticed that the cells have been caught in an early stage of the cell cycle: both unable to synthesize new DNA or proceed to cell division.
A fancy course of that begins with a mannose oversupply freezes the cells in a state that they’ll’t develop out of. In subsequent experiments, the staff pinned this all the way down to mannose extra altering the metabolism of most cancers cells. Particularly, it prevents the manufacturing of nucleotides, the constructing blocks of DNA.
It’s this shortage of nucleotides that underlies the anticancer property of mannose. Apart from the synthesis of latest DNA, the equipment that repairs injury in DNA additionally requires nucleotides. At excessive mannose ranges, most cancers cells can’t restore the DNA injury brought on by anti-cancer medication, enhancing their efficacy.
Mannose remedy could possibly be significantly efficient for cancers which have low exercise of the MPI enzyme. Alternatively, medication that decrease nucleotide ranges in most cancers cells are additionally promising. “We now have developed most cancers organoids from sufferers [and] we are actually testing if these medication can improve chemotherapy,” Harada added.
Presently, mannose finds use within the remedy of sufferers affected by congenital issues of glycosylation (CDG), marked by faulty mannose metabolism. However, a steep enhance of mannose within the blood following remedy causes poisonous negative effects as a result of its structural similarity with glucose.
In future work, the staff plans to look deeper into the molecular hyperlinks between mannose extra and a scarcity of nucleotides. This might pave the best way for the event of medicine, for each cancers and CDG, which have the advantages of mannose with out its toxicity.
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Supply: Osaka International Cancer Institute ; Picture: Wikimedia Commons
The paper might be discovered at: Metabolic clogging of mannose triggers dNTP loss and genomic instability in human cancer cells | eLife
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