• androstene steroids;
  • apoptosis;
  • autophagy;
  • glioblastoma;
  • lymphoma;
  • structure-activity

Androstene steroids are metabolites of dehydroepiandrosterone and exist as androstene-diols or -triols in α- and β-epimeric forms based upon the placement of the hydroxyl groups relative to the plane of the Δ5cycloperhydrophenanthrene ring. 5-Androstene-3β,17β-diol (3β,17β-AED) functions to upregulate immunity and the addition of a third hydroxyl group at C-7 in the α- or β-orientation (3β,7α,17β-AET and 3β,7β,17β-AET, respectively) enhances the immunological activity of the molecule. In contrast, 5-androstene-3β,17α-diol (3β,17α-AED) possesses potent anti-tumor activity. We synthesized a new androstene by adding a third hydroxyl group at C-7 to make 5-androstene-3β,7α,17α-triol (3β,7α,17α-AET) and compared the anti-tumor activity of this steroid to the four existing androstenes. The results showed that this modification reduced the activity of 3β,17α-AED. The ranking of the anti-tumor activities of these steroids and their IC50 on human glioblastoma and lymphoma cells was: 3β,17α-AED (∼10 μm) > 3β,7α,17α-AET (∼30 μm) >> 3β,7α,17β-AET (∼150 μm)> 3β,7β,17β-AET (not achievable) ≥ 3β,17β-AED (not achievable). 3β,17α-AED and 3β,7α,17α-AET induced autophagy in T98G glioblastoma cells and apoptosis in U937 lymphoma cells. These results indicate that the position of the hydroxyl group on C-17 dictates the anti-tumor activity of the androstenes and must be in the α-configuration, demonstrating a strict structure–activity relationship.