Authors: Graf, Martin R.; Jia, Wentao¹; Lewbart, Marvin L.²; Loria, Roger M.³

Source: Chemical Biology & Drug Design, Volume 74, Number 6, December 2009 , pp. 625-629(5)

Publisher: Wiley-Blackwell

Abstract:

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.

Keywords: androstene steroids; apoptosis; autophagy; glioblastoma; lymphoma; structure-activity

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1747-0285.2009.00900.x

Affiliations: 1: Department of Neurosurgery - Harold F. Young Neurosurgical Center and the Massey Cancer Center, Virginia Commonwealth University Medical Center, P.O. Box 980631, 1200 E. Broad Street, Richmond, VA 23298-0631, USA 2: Custom Steroid Synthesis, Voorhees, NJ, USA 3: Departments of Microbiology and Immunology, Pathology and Emergency Medicine, Virginia Commonwealth University Medical Center, Richmond, VA, USA

Publication date: 2009-12-01

Related content

• In this: publication
• By this: publisher
• In this Subject: Chemistry ,  Pharmacology ,  Biochemistry
• By this author: Graf, Martin R. ;  Jia, Wentao ;  Lewbart, Marvin L. ;  Loria, Roger M.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers