This Article Full Text (Online First [PDF]) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Arafa, E.-S. A. Articles by Wani, A. A. PubMed PubMed Citation Articles by Arafa, E.-S. A. Articles by Wani, A. A.

Tangeretin Sensitizes Cisplatin-Resistant Human Ovarian Cancer Cells through Downregulation of Phosphoinositide 3-Kinase/Akt Signaling Pathway

Division of Radiobiology, Department of Radiology, The Ohio State University, Columbus, Ohio

Requests for reprints: Altaf A. Wani or Mohamed A. El-Mahdy, Division of Radiobiology, Department of Radiology, The Ohio State University, Room 720, 460 West 12th Avenue, Columbus, OH 43210. Phone: 614-292-9015; Fax: 614-292-9201; E-mail: wani.2{at}osu.edu or Mohamed.el-mahdy{at}osumc.edu.

Combination of innocuous dietary components with anticancer drugs is an emerging new strategy for cancer chemotherapy to increase antitumor responses. Tangeretin is a citrus flavonoid known to inhibit cancer cell proliferation. Here, we show an enhanced response of A2780/CP70 and 2008/C13 cisplatin-resistant human ovarian cancer cells to various combination treatments of cisplatin and tangeretin. Pretreatment of cells with tangeretin before cisplatin treatment synergistically inhibited cancer cell proliferation. This combination was effective in activating apoptosis via caspase cascade as well as arresting cell cycle at G₂-M phase. Moreover, phospho-Akt and its downstream substrates, e.g., NF-B, phospho-GSK-3β, and phospho-BAD, were downregulated upon tangeretin-cisplatin treatment. The tangeretin-cisplatin–induced apoptosis in A2780/CP70 cells was increased by phosphoinositide-3 kinase (PI3K) inhibition and siRNA-mediated Akt silencing, but reduced by overexpression of constitutively activated Akt and GSK-3β inhibition. The overall results indicated that tangeretin exposure preconditions cisplatin-resistant human ovarian cancer cells for a conventional response to low-dose cisplatin-induced cell death occurring through downregulation of PI3K/Akt signaling pathway. Thus, effectiveness of tangeretin combinations, as a promising modality in the treatment of resistant cancers, warrants systematic clinical studies. [Cancer Res 2009;69(23):OF1–8]

Key Words: Cisplatin • ovarian cancer • tangeretin