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Investigating Molecular Targets of Phosphaplatins: A Class of Novel Non-DNA-Binding Platinum Anticancer Agents in the Treatment of Ovarian Cancer

Majmudar, Pooja M.
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1300373466

Abstract Details

2011, Doctor of Philosophy (PhD), Ohio University, Molecular and Cellular Biology (Arts and Sciences).
Platinum drugs have been the cornerstone in treating human ovarian cancer, as a result of major advances in the field of synthetic and analytical chemistry. Drugs such as cisplatin and carboplatin that are routinely used for chemotherapy, form intra- and inter-strand platinum-DNA cross links, ultimately leading to cancer cell death. But unfortunately in many cases this platinum-DNA association is also responsible for treatment resistance, leading to patient death. It has been extensively documented that inhibition of DNA repair pathways and a greater understanding of cellular reactions upon platinum drug treatment, are crucial in diminishing toxicity and improving the effectiveness of such drugs. Pyrodach-2, belonging to a class of novel platinum compounds called phosphaplatins, demonstrated enhanced cytotoxicity against ovarian cancer cells and no DNA-binding in a recently published study (Bose et. al., 2009). These observations inspired the following study, which aims at determining the anti-cancer properties of two other pyrophosphate complexes, namely pyrodach-4 and RRD4. Platinum compounds have been known to channel their effects through multiple pathways. In the first part of this study, the signaling mechanism(s) of pyrodach-4, which induced ovarian cancer cell death upon treatment, were investigated. Cell-death and apoptosis associated genes along with their products make good targets, which can be exploited in the development of drugs to treat human diseases. Using various assays such as gene expression microarray and qRT-PCR, levels of various such genes were analyzed. Interestingly pyrodach-4 utilized genes belonging to both the extrinsic and intrinsic apoptotic cell death machinery, namely Bax, Fas, PTEN and PUMA to induce maximal cisplatin-sensitive and -resistant ovarian cancer cell death at 24 hours post treatment. Further, anti-apoptotic genes such as Bcl-2 decreased in treated cells. In contrast, protein expression results for Fas and Bax proteins did not exactly mimic the results from the gene expression analyses, suggesting that post-transcriptional modifications might be at play. Additionally, findings from investigating RRD4 cytotoxicity, suggested that both the cisplatin-sensitive and resistant cell lines were sensitive to 24 hour treatment with RRD4. Combined results from the gene expression, protein expression and ELISA analyses proved that RRD4-treated cells may be differentially regulated than those treated with pyrodach-4, hinting a faster uptake process, and a distinct mechanism of action of RRD4, in comparison to pyrodach-4. Effects of platinum drugs on tumor vasculature have become the subject of increased study. In part two of this study, treatment of HUVECs with pyrodach-4 and RRD4 caused intense cell death, adding anti-angiogenesis to the repertoire of phosphaplatin anti-cancer functions. Finally, in accordance with the anti-cancer activities seen in vitro, pyrodach-4 toxicity and efficacy studies were performed, as the third part of the study. Results from the toxicity and efficacy studies demonstrated that phosphaplatins were well tolerated and performed much better in comparison to cisplatin- and carboplatin-treated mice. Collectively, data presented in this study reveal the probable pathways triggered upon pyrodach-4 and RRD4 treatments, making phosphaplatins a class of novel targeted compounds, which can be used to treat human ovarian cancer.
Rathindra Bose, PhD (Advisor)
Monica Burdick, PhD (Committee Member)
Stephen Bergmeier, PhD (Committee Member)
Douglas Goetz, PhD (Committee Member)
Shiyong Wu, PhD (Committee Member)
200 p.
Cellular Biology; Molecular Biology
Ovarian Cancer; Platinum drugs; Phosphaplatin; Cisplatin; Carboplatin; Anti-angiogenesis

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Citations

  • Majmudar, P. M. (2011). Investigating Molecular Targets of Phosphaplatins: A Class of Novel Non-DNA-Binding Platinum Anticancer Agents in the Treatment of Ovarian Cancer [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1300373466

    APA Style (7th edition)

  • Majmudar, Pooja. Investigating Molecular Targets of Phosphaplatins: A Class of Novel Non-DNA-Binding Platinum Anticancer Agents in the Treatment of Ovarian Cancer. 2011. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1300373466.

    MLA Style (8th edition)

  • Majmudar, Pooja. "Investigating Molecular Targets of Phosphaplatins: A Class of Novel Non-DNA-Binding Platinum Anticancer Agents in the Treatment of Ovarian Cancer." Doctoral dissertation, Ohio University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1300373466

    Chicago Manual of Style (17th edition)

ohiou1300373466
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© 2011, all rights reserved.
This open access ETD is published by Ohio University and OhioLINK.