Mechanistic investigation of an anticancer agent that damages DNA and interacts with the androgen receptor

The 11[beta] molecule comprises a ligand for the androgen receptor (AR), which is crucial to progression and survival of many prostate cancers, tethered to a DNA-damaging aniline mustard. The compound was designed to exhibit selective toxicity toward prostate cancer cells by forming sites of 11[beta]P -DNA damage to which AR binds, physically blocking access of repair enzymes while becoming unavailable to activate transcription of pro-survival genes. Previous studies have demonstrated the ability of 11[beta] 3 to damage DNA, retain affinity for AR when covalently adducted to DNA, and prevent selectively the growth of prostate xenograft tumors implanted in mice. Here we demonstrate that 11[beta] promotes phosphorylation and nuclear localization of AR, resulting in receptor association with androgen response elements. However, 11[beta] 3 only weakly drives AR transcriptional activity, and instead moderately antagonizes AR-mediated transcription elicited by natural androgens. Furthermore, 11[beta]0 dramatically decreases steady-state levels of AR protein. Collectively, these activities limit the expression of androgen-regulated genes and could control toxicity in AR-expressing prostate cancers. Despite possessing an ability to modulate AR transcriptional activity, 11[beta]0 is not selectively toxic toward the AR-positive member of an otherwise isogenic pair of prostate cancer cell lines derived from PC3 cells, which do not depend on AR-mediated gene expression for growth or survival. Therefore, the extraneous presence of AR does not increase 11[beta]13 toxicity.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2009

Author dc:creator

• Proffitt, Kyle David

Advisor dc:contributor.advisor

• John Martin Essigmann.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/49747

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/49747