Targeting CD38 in the tumor microenvironment; a novel approach to treat glioma

Abstract

Glioblastoma multiforme (GBM) is one of the most lethal human cancers, accounting for about 15% of all primary brain tumors in adults. Tumor-associated microglia/macrophages (TMMs) are a major constituent of the tumor mass and the tumor microenvironment where they support tumor progression. We previously demonstrated that the NAD + utilizing ectoenzyme CD38 regulates microglia activation and that loss of CD38 inhibits glioma progression and extends the survival of glioma-bearing mice. These results indicated that targeting CD38 in the tumor microenvironment may serve as a novel therapeutic approach to treat glioma. To test this hypothesis, we identified small molecules that inhibit CD38 enzymatic activity (NAD + glycohydrolase): the natural anthranoid rhein, its water-soluble tri-potassium salt (K-rhein), and the polyphenol tannic acid (TA). Microglial properties regulated by CD38 (e.g., NO secretion and LPS/IFN activation induced cell death) were inhibited in primary microglia treated with rhein in a CD38-dependent manner. Furthermore, wild-type mice intracranially injected with GL261 mouse glioma cells and intranasally treated with K-rhein or TA, exhibited significant reduction in tumor volume and prolonged life-span compared to vehicle treated mice. On the other hand, these inhibitors had only a modest effect on tumor-bearing Cd38 / mice. Taken together, our results demonstrate that small molecule CD38 inhibitors such as K-rhein and TA can target CD38 in the tumor microenvironment and offer a novel and useful strategy for glioma treatment.

Targeting CD38 in Neoplasms and Non-Cancer Diseases

“…The variety of inhibitors of CD38 (smCD38i) includes two main functional groups of compounds: covalent inhibitors, which form a bond in the active site at Glu226, and non-covalent inhibitors, which bind to amino acid residues in the active site of the enzyme by weaker interactions [ 26 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. When it comes to compounds’ chemical structures, there are flavonoids (apigenin, quercetin, and leteolinidin), heterocycles compounds (derivatives of 4-amino-quinoline), and NAD-analogues (carba-NAD and ara-NAD analogs).…”