Androstene
steroids are metabolites of
dehydroepiandrosterone and exist as androstene-diols or -triols in alpha- and beta-epimeric forms based upon the placement of the
hydroxyl groups relative to the plane of the Delta(5)cycloperhydrophenanthrene ring. 5-Androstene-3beta,17beta-diol (3beta,17beta-AED) functions to upregulate immunity and the addition of a third
hydroxyl group at C-7 in the alpha- or beta-orientation (3beta,7alpha,17beta-
AET and 3beta,7beta,17beta-
AET, respectively) enhances the immunological activity of the molecule. In contrast, 5-androstene-3beta,17alpha-diol (3beta,17alpha-AED) possesses potent anti-
tumor activity. We synthesized a new androstene by adding a third
hydroxyl group at C-7 to make 5-androstene-3beta,7alpha,17alpha-triol (3beta,7alpha,17alpha-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 3beta,17alpha-AED. The ranking of the anti-
tumor activities of these
steroids and their IC50 on human
glioblastoma and
lymphoma cells was: 3beta,17alpha-AED ( approximately 10 microm) > 3beta,7alpha,17alpha-AET ( approximately 30 microm) " 3beta,7alpha,17beta-AET ( approximately 150 microm)> 3beta,7beta,17beta-AET (not achievable) >or= 3beta,17beta-AED (not achievable). 3beta,17alpha-AED and 3beta,7alpha,17alpha-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 alpha-configuration, demonstrating a strict structure-activity relationship.