Inhibition of glioma progression by a newly discovered CD38 inhibitor

Eran Blacher, Bar Ben Baruch, Ayelet Levy, Nurit Geva, Keith D. Green, Sylvie Garneau-Tsodikova, Micha Fridman, Reuven Stein

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1422-1433
Number of pages12
JournalInternational Journal of Cancer
Volume136
Issue number6
DOIs
StatePublished - 15 Mar 2015

Keywords

  • Brain tumors
  • Microglia
  • Rhein
  • Tumor microenvironment

Fingerprint

Dive into the research topics of 'Inhibition of glioma progression by a newly discovered CD38 inhibitor'. Together they form a unique fingerprint.

Cite this