title: Inhibition of glioma progression by a newly discovered CD38 inhibitor.
abstract: Glioma, the most common cancer of the central nervous system, has very poor prognosis and no effective treatment. It has been shown that activated microglia/macrophages in the glioma tumor microenvironment support progression. Hence, inhibition of the supporting effect of these cells may constitute a useful therapeutic approach. Recently, using a syngeneic mouse glioma progression model, we showed that the ectoenzyme CD38 regulated microglia activation and, in addition, that the loss of CD38 from the tumor microenvironment attenuated glioma progression and prolonged the life span of the tumor-bearing mice. These studies, which employed wild-type (WT) and Cd38(-/-) C57BL/6J mice, suggest that inhibition of CD38 in glioma microenvironment may be used as a new therapeutic approach to treat glioma. Our study tested this hypothesis. Initially, we found that the natural anthranoid, 4,5-dihydroxyanthraquinone-2-carboxylic acid (rhein), and its highly water-soluble tri-potassium salt form (K-rhein) are inhibitors of CD38 enzymatic (nicotinamide adenine dinucleotide glycohydrolase) activity (IC50 = 1.24 and 0.84 μM, respectively, for recombinant mouse CD38). Treatment of WT, but not Cd38(-/-) microglia with rhein and K-rhein inhibited microglia activation features known to be regulated by CD38 (lipopolysaccharide/IFN-γ-induced activation, induced cell death and NO production). Furthermore, nasal administration of K-rhein into WT, but not Cd38(-/-) C57BL/6J, mice intracranially injected with GL261 cells substantially and significantly inhibited glioma progression. Hence, these results serve as a proof of concept, demonstrating that targeting CD38 at the tumor microenvironment by small-molecule inhibitors of CD38, for example, K-rhein, may serve as a useful therapeutic approach to treat glioma.
authors: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel.
authors: Eran
authors: E
authors: Blacher
authors: Bar
authors: B
authors: Ben Baruch
authors: Ayelet
authors: A
authors: Levy
authors: Nurit
authors: N
authors: Geva
authors: Keith D
authors: KD
authors: Green
authors: Sylvie
authors: S
authors: Garneau-Tsodikova
authors: Micha
authors: M
authors: Fridman
authors: Reuven
authors: R
authors: Stein
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D016207:Cytokines; D018450:Disease Progression; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis; D014452:Ubiquitins
chemical_list: D000880:Anthraquinones; D016207:Cytokines; C489550:G1p2 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D014452:Ubiquitins; D009569:Nitric Oxide; D007371:Interferon-gamma; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; C020491:rhein
keywords: brain tumors; microglia; rhein; tumor microenvironment