Novel Preclinical Anti-Glioma Steroid Biosynthesis Inhibitor Identified
In vitro, DK16 decreases glioma tumor cell viability, proliferation, and migration, the authors reported.
“Our findings collectively demonstrate the potent anti-neoplastic properties of DK16, a steroid biosynthesis inhibitor, on the growth of pediatric low grade gliomas,” reported senior author Deepak Kamnasaran, MD, PhD, of the Department of Pediatrics at Laval University in Québec, Canada, and coauthors. “DK16, an inhibitor of 17β-HSD3 (17β-hydroxysteroid dehydrogenase type 3), can modulate the expression of several oncogenic mediators leading to decreased cell viability, proliferation and migration/invasion, and the induction of growth arrest and apoptosis.”
DK16 “efficiently” crosses the blood brain barrier and “can significantly inhibit anchorage-independent growth,” the authors reported.
Steroid biosynthesis is suspected to play a role in glioma growth, prompting the authors' search for steroid inhibitors that can affect glioma cell behavior. The team identified “a potent inhibitor of 17β-HSD3,” referred to as DK16, which triggers apoptosis and cell-cycle arrest “in a dose- and duration-dependent manner”, the authors reported. Significant changes indicative of apoptosis were noted in 5 days after augmenting test doses (P<0.0001).
The drug leads to depolarization of tumor mitochondrial membranes, they noted.
Treating low grade glioma cell lines with DK16 “increased the expression of pro-apoptotic mediators including CDK2 and CTSL1, and with the converse diminished expression of pro-survival and migratory/invasion genes like PRKCA, TERT, MAPK8, MMP1 and MMP2,” reported the authors. In all, DK16 significantly up- or down-regulated by more than two-fold, the expression of 26 genes associated with cell apoptosis, proliferation, migration and invasion, cell cycle, transformation, and DNA repair, they wrote.
“Collectively, these robust pre-clinical findings extend promising results on the potent anti-neoplastic properties of DK16 in the treatment of pediatric low grade gliomas,” the authors concluded.