New York : High doses of vitamin C may halt the progression of a deadly blood cancer by encouraging faulty stem cells in the bone marrow to die, a study claims.
Certain genetic changes are known to reduce the ability of an enzyme called TET2 to encourage stem cells to become mature blood cells, which eventually die, in many patients with certain kinds of leukaemia, researchers said.
“We are excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukaemia stem cells, most likely in combination with other targeted therapies,” said Benjamin Neel, professor at New York University (NYU) in the US.
Changes in the genetic code (mutations) that reduce TET2 function are found in 10 per cent of patients with acute myeloid leukaemia (AML), 30 per cent of those with a form of pre-leukaemia called myelodysplastic syndrome, and in nearly 50 per cent of patients with chronic myelomonocytic leukaemia.
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Such cancers cause anaemia, infection risk, and bleeding as abnormal stem cells multiply in the bone marrow until they interfere with blood cell production, with the number of cases increasing as the population ages. Researchers studied the relationship between TET2 and cytosine, one of the four nucleic acid “letters” that comprise the DNA code in genes.
To determine the effect of mutations that reduce TET2 function in abnormal stem cells, the team genetically engineered mice such that the scientists could switch the TET2 gene on or off. They found that similar to the naturally occurring effects of TET2 mutations in mice or humans, using molecular biology techniques to turn off TET2 in mice caused abnormal stem cell behaviour. These changes were reversed when TET2 expression was restored by a genetic trick.
Previous studies had shown that vitamin C could stimulate the activity of TET2 and its relatives TET1 and TET3. Since only one of the two copies of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, researchers hypothesised that high doses of vitamin C, which can only be given intravenously, might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.
They found that vitamin C did the same thing as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C treatment induced stem cells to mature, and also suppressed the growth of leukaemia cancer stem cells from human patients implanted in mice. “Interestingly, we also found that vitamin C treatment had an effect on leukemic stem cells that resembled damage to their DNA,” said Luisa Cimmino, assistant professor at NYU Langone Health.
Researchers combined vitamin C with a PARP inhibitor, a drug type known to cause cancer cell death by blocking the repair of DNA damage. They found that the combination had an enhanced effect on leukaemia stem cells, further shifting them from self-renewal back toward maturity and cell death.
The results also suggest that vitamin C might drive leukemic stem cells without TET2 mutations toward death, given that it turns up any TET2 activity normally in place, Cimmino said. The study was published in the journal Cell.