Cellular response to 11[beta]-dichloro, a novel aniline mustard-estradienone, in various prostate cancer cell lines

Cancer is a group of diseases characterized by uncontrolled cell growth and abnormal cell cycle and apoptosis regulation. Among the types of cancer, prostate cancer is the leading cause of death in men. Although many advances have been made in the last decade through anti-hormonal treatment, chemotherapy, and early screening, acquired chemotherapeutic resistance has presented a challenge to treating more advanced forms of prostate cancer. To meet this challenge a new compound, 11[beta]-dichloro, was designed that would integrate lessons learned from previous studies with other chemotherapuetics, specifically cisplatin. 11[beta]-dichloro is a novel aniline mustardestradienone that targets both DNA and the androgen receptor (AR), which is over expressed in many types of prostate cancer. The working hypothesis is that by causing substantial amount of un-repairable DNA damage and sequestering the transcription factor function of the androgen receptor it would result in a more effective treatment when compared to existing treatments. Hence, 11 [beta]-dichloro is expected to affect ARpositive prostate cancer cells more robustly than AR-negative cells, based on our repair shielding and transcription factor hijacking hypotheses. To assay differential toxicity, five different prostate cancer cell lines were used, namely, LNCaP (AR-positive, T887A), PC3 (AR-negative, p53 inactive), DU145 (AR-negative, p53 null), and the isogenic pair PC3-AR (AR-positive) and PC3-neo (AR-negative), which only differ in the AR status. Growth inhibition with LNCaP, PC3, and DU 145 cells showed that LNCaP cells are more sensitive to 11 [mu]-dichloro at concentrations higher than 5.0 tM. To better assay the effect of the AR in cell survival a clonogenic assay was developed using PC3-AR and PC3-neo cells. Preliminary growth inhibition studies with this isogenic pair showed differential toxicity towards AR-positive PC3-AR cells up to 10 [mu]M 11 [beta]-dichloro.

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

• González, Francis Héber

Advisor dc:contributor.advisor

• John 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/1721.1/46652

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/46652