AI Article Synopsis

  • Supplementation with non-toxic doses of selenium has been found effective in mice for reducing chronic myelogenous leukemia (CML) by targeting leukemia stem cells (LSCs), which are often resistant to current treatments.
  • The mechanism involves the production of cyclopentenone prostaglandins (CyPGs) that activate the PPARγ receptor; blocking this pathway with GW9662 eliminates the antileukemic benefits of selenium.
  • Additionally, using a PPARγ agonist like pioglitazone mirrors the effects of selenium by lowering the activity of 15-prostaglandin dehydrogenase (15-Pgdh), which reduces CyPG levels and inhibits CML progression.

Article Abstract

Supplementation with nontoxic doses of micronutrient selenium has been shown to alleviate chronic myelogenous leukemia (CML) via the elimination of leukemia stem cells (LSCs) in mice. This treatment provides a new and novel method for eliminating the LSCs that are otherwise not targeted by existing therapies. The antileukemic effect of selenium was dependent on the production of endogenous cyclopentenone prostaglandins (CyPGs), Δ-12 prostaglandin J (Δ-PGJ), and 15-deoxy-Δ12,14-prostaglandin J (15d-PGJ). Here, we show that these endogenous CyPGs, produced by mice maintained on selenium-supplemented diets, alleviate the symptoms of CML through their ability to activate the nuclear hormone receptor, peroxisome proliferator activated receptor γ (PPARγ). GW9662, a potent PPARγ antagonist, blocked the antileukemic effect of selenium supplementation by significantly reducing CyPGs. This effect was mediated by an increase in 15-prostaglandin dehydrogenase (15-Pgdh) activity, which oxidizes and inactivates Δ-PGJ and 15d-PGJ In contrast, treatment with the PPARγ agonist pioglitazone mimicked selenium supplementation. This treatment led to decreased 15-Pgdh activity and increased CyPG levels, which inhibited CML progression. Selenium-dependent activation of PPARγ mediated by endogenous CyPGs decreased Stat5 expression leading to the downregulation of Cited2, a master regulator of LSC quiescence. These studies suggest a potential role for selenium supplementation as an adjuvant therapy in CML.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374288PMC
http://dx.doi.org/10.1182/blood-2016-08-736405DOI Listing

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