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Paclitaxel (PTX) is an effective anti-mitotic drug. It stops cancer from spreading by interfering with the microtubule dynamics which in turn leads to cell cycle arrest and eventually cell death. Despite the clinical success in treating different types of cancers, resistance to PTX remains a major hurdle for successful treatment in relapse patients. Albendazole (ABZ) is a popular anthelmintic used world-wide for the treatment of various types of helmintic infections. In helminthes, ABZ binds to ??-tubulin and inhibits microtubule polymerisation. It was subsequently found that ABZ has anti-cancer activity. This study was carried out to study the effects of ABZ on PTX sensitive and PTX resistant human ovarian carcinoma cells. Cell growth assays revealed that the anti-proliferative activity of ABZ was not only effective on the PTX-sensitive human ovarian carcinoma cell line lA9, but also on its PTX-resistant sub-line, lA9PTX22. The ICso values of ABZ in lA9 and lA9PTX22 were 205 nM and 322 nM, respectively. Confocal images demonstrated that ABZ disrupted the microtubule network and caused formation of short microtubule bundles in both cell lines. Further analysis using tubulin polymerisation assay showed that the percentage of polymerised tubulin in lA9 and lA9PTX22 was increased by 58.9 % and 20.6 % respectively. Together, these results revealed for the first time that ABZ interacts with microtubules in human cancer cells and causes their polymerisation. It was also demonstrated that ABZ increased the release of cytochrome c, an important component of the intrinsic pathway in apoptosis. It was found that the expression of Bim, a BH-3 only pro-apoptotic protein was not elevated after ABZ treatment. The results presented in this study provide some information on the effect of ABZ on the microtubule network which could relate to its apoptotic effect in human ovarian carcinoma cells.

[Truncated abstract] Ovarian cancer is currently the leading cause of death from gynaecological malignancies in women from developed countries. Serous ovarian cancer is the most prevalent type of all ovarian cancers, with the majority diagnosed in an advanced stage where treatment efficacy is reduced and patient survival is poor. Because of this fact, the development of improved detection and treatment strategies are necessary, with much research focussing on the complex molecular pathways involved in ovarian tumour growth as one potential avenue for intervention. Apoptosis, or programmed cell death, is one such area of investigation because currently successful cancer treatments induce apoptosis in tumour cells. Molecular analysis of apoptosis in both normal tissue and tumours has established a positive relationship between increased expression of secreted frizzled-related protein 4 (SFRP4) and apoptosis, however to date, very little research has focussed on the role of this gene in the ovary . . . An examination of SFRP4 and β-catenin expression in 163 primary serous ovarian carcinomas revealed high SFRP4 expression was associated with low β-catenin expression and conversely, low SFRP4 was associated with high β-catenin expression in the majority of the ovarian tumours analysed, reinforcing the inverse relationship observed in the ovarian cell lines. A positive trend was observed between cancer stage and the expression level of these proteins, with increased SFRP4 expression and reduced β-catenin expression as cancer stage increased. Additionally, patient survival revealed a trend towards increased survival among ovarian cancer patients who had tumours expressing low levels of SFRP4. Taken together, the novel findings of this study indicate that the increased expression of SFRP4 observed in a large proportion of serous ovarian cancers is a cellular response to down-regulate the level of β-catenin, and thus an attempt to maintain cellular homeostasis by counteracting the excessive proliferating signals present in these tumour cells.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2005. / Härtill 4 uppsatser.

Thesis (M. Med. Sc.)--University of Hong Kong, 2007.

Thesis (Ph.D.)--University of Melbourne, Peter MacCallum Cancer Centre and The Dept. of Biochemistry and Molecular Biology, 2006. / Typescript. Includes bibliographical references (leaves 281-331).

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 160-184) Also available in print.

Thesis (Ph. D.)--University of Missouri-Columbia, 2000. / Typescript. Vita. Includes bibliographical references (leaves 137-162). Also available on the Internet.

Thesis (M. Med. Sc.)--University of Hong Kong, 2004. / Also available in print.

Thesis (Ph.D.) - University of Queensland, 2004. / Includes bibliography.