All ETDs from UAB

Advisory Committee Chair

Trygve O Tollefsbol

Advisory Committee Members

Charles N Landen

Ronald D Alvarez

Thane Wibbels

Yuanyuan Li

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

The cellular development of resistance to chemotherapy contributes to the high mortality noted in patients affected by ovarian cancer. Novel compounds that can enhance efficacy of conventional chemotherapy or target both drug-sensitive and -resistant ovarian cancers directly are highly desired. Previous epidemiological studies indicate that consumption of green tea and cruciferous vegetables is inversely associated with occurrence of ovarian cancer. Therefore, revealing the effects and mechanisms of major components of green tea (epigallocatechin gallate, EGCG) and cruciferous vegetables (sulforaphane, SFN) on ovarian cancer cells will provide necessary knowledge for developing potential novel treatments for the disease. Since drug resistance generation is related to alterations of multiple cell survival pathways besides changes in pharmacokinetic pathways, combinational treatment targeting multiple pathways simultaneously is a promising strategy for therapy of drug-resistant ovarian cancer. In this study, EGCG or SFN was administered alone or in combination to treat both cisplatin/paclitaxel-sensitive and -resistant ovarian cancer cell lines. We found that SFN inhibits cell viability of both ovarian cancer cell lines time- and dose-dependently and EGCG can potentiate the inhibiting effect of SFN. In cisplatin-sensitive and -resistant ovarian cancer cells, SFN can arrest cancer cells in G2/M phase, and EGCG can enhance the SFN-mediated G2/M phase arresting effect. Furthermore, EGCG and SFN combinational treatment can enhance cisplatin-mediated apoptosis in cisplatin-sensitive and -resistant ovariance cancer cells through enhancing G2/M phase arrest and p21 upregulation. In paclitaxel-resistant ovarian cancer cells, SFN can induce cancer cells to undergo apoptosis, while EGCG can enhance SFN-mediated apoptosis. SFN can arrest both paclitaxel-sensitive and -resistant ovarian cancer cells in G2/M phase. However, EGCG and SFN combinational treatment can arrest more cells in S phase but fewer cells in G2/M phase. On molecular level, SFN can down-rgulate hTERT and Bcl-2 while upregulating phosphorylated H2AX and cleaved poly(ADP-ribose) polymerase (PARP) which is a indicator for apoptosis. EGCG can enhance these SFN-mediated effects. Taken together, these results indicate that EGCG can potentiate SFN-mediated inhibiting effect on both cisplatin/paclitaxel-sensitive and -resistant ovarian cancer cell lines and suggest the use of these compounds for overcoming cisplatin/paclitaxel-resistance in ovarian cancer treatment.

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