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Targeting Prostate Cancer by Small Molecules

Zhang, Jian
http://rave.ohiolink.edu/etdc/view?acc_num=case1300808547

Abstract Details

2011, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
Prostate cancer (PCa) is the most common malignant tumor and one of the most frequent causes of mortality for men in the US. This project is focused on exploration of the idea of “anti-tissue therapy”, which involves the identification and use of compounds that can selectively eliminate cells of prostate origin. The feasibility of this approach is justified by the success of anti-androgen therapy, which targets all cells of prostate lineage. Unfortunately, androgen ablation therapy is effective only at early stages of the disease and results in the development of hormone-independent tumors that are practically insensitive to available therapies. By screening diverse chemical libraries a series of compounds were identified that belonged to five structural classes, which are specifically toxic towards androgen receptor (AR) expressing PCa cells, particularly 22Rv1 cells. In particular, these compounds, designated ARKILs, demonstrated extremely strong selective toxicity to 22Rv1 cells that involved cell cycle arrest and apoptosis. ARKILs have no effect on the stability of AR protein or AR mRNA. In addition, they do not block AR translocation into the nucleus. However, they clearly inhibit AR mediated transcription. The degree of resistance of the isolated 22Rv1 cell variants to ARKILs was comparable to that of non-prostate origin cells. Moreover, the variants selected with a single ARKIL were cross-resistant to all others. This cross-resistance does not appear to be mediated by ATP-dependent multidrug resistance (MDR) transporters (P-gp/MRPs). ARKILs are likely to target one common mechanism that is important to survival of 22Rv1 cells. siRNA against AR did not sensitize resistant variants (AKRVs) to ARKILs, suggesting that the target is not AR itself. However, mechanism(s) of action of ARKILS may involve a component(s) of the AR signalling pathway. The therapeutic potential of ARKILs against PCa was evaluated with 22Rv1 xenografts in nude mice. ARKIL-3 showed modest, but statistically insignificant, inhibition of 22Rv1 xenograft tumors but may yield promising efficacy in following future optimization. ARKIL-8 is able to block growth of and even kill PCa tumors. Therefore, ARKILs, as represented by ARKIL-3 and ARKIL-8, have potential for development into therapeutic agents against PCa.
Andrei Gudkov (Advisor)
David Samols (Committee Chair)
Donal Luse (Committee Member)
Hung-Ying Kao (Committee Member)
Julia Kichina (Committee Member)
Warren Heston (Committee Member)
209 p.
Cellular Biology
prostate cancer; androgen receptor; AR; drug discovery

Recommended Citations

Citations

  • Zhang, J. (2011). Targeting Prostate Cancer by Small Molecules [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1300808547

    APA Style (7th edition)

  • Zhang, Jian. Targeting Prostate Cancer by Small Molecules. 2011. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1300808547.

    MLA Style (8th edition)

  • Zhang, Jian. "Targeting Prostate Cancer by Small Molecules." Doctoral dissertation, Case Western Reserve University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1300808547

    Chicago Manual of Style (17th edition)

case1300808547
559
© 2011, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.