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

Abstract

Combination of innocuous dietary components with anticancer drugs is an emerging new strategy for cancer chemotherapy to increase anti-tumor responses. Tangeretin (TG) 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 (Cis) and tangeretin. Pretreatment of cells with tangeretin prior to 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-κB, phospho-GSK-3β and phospho-BAD were down-regulated 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 over-expression 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 down-regulation of PI3K/Akt signaling pathway. Thus, effectiveness of tangeretin combinations, as a promising modality in the treatment of resistant cancers, warrants systematic clinical studies.

HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition

“…24,42,43 Tangeretin, a citrus flavonoid, has been reported to produce a synergistic effect with cisplatin by inhibiting the PI3K/Akt-signaling pathway, and induction of apoptosis in ovarian cancer cells. 29 Our results suggest that the DAPs are also effective in enhancing the treatment of drug resistant ovarian cancer when used in combination with cisplatin when compared with cisplatin alone. To our knowledge, this is the first report demonstrating the potential of a curcumin analog to function as a chemosensitizer for ovarian cancer treatment.…”

“…Earlier studies have indicated that resistance to chemotherapy-induced apoptosis in ovarian cancer cell lines and tumor growth can be overcome by co-treatment with other anticancer agents. 25,29,35,36 Co-administration of cisplatin with paclitaxel has routinely been used for recurrent ovarian cancer. 3,6 The present study provides experimental evidence that the curcumin analogs H-4073 and HO-3867 are able to enhance the therapeutic potential of cisplatin in drug-resistant ovarian cancer cells.…”

Dietary flavonoid tangeretin induces reprogramming of epithelial to mesenchymal transition in prostate cancer cells by targeting the PI3K/Akt/mTOR signaling pathway

“…In the present study, the anticancer potential of tangeretin, a 4',5,6,7,8-pentamethoxyflavone, against prostate carcinoma was investigated. Although tangeretin has been suggested to be effective against several types of cancer (22)(23)(24)(25), its role against prostate cancer has not been determined and requires additional investigation.…”

A unique histone deacetylase inhibitor alters microRNA expression and signal transduction in chemoresistant ovarian cancer cells

“…6 Additionally, while we did not examine Akt signaling in the current study, others have demonstrated that Akt signal inhibition (by AR42 and other agents) sensitized CP70 and other p53-dysfunctional, drug-resistant, ovarian cancer cells. 37,56 As AR42 has also been demonstrated to downregulate Akt activity, [7][8][9]12 blockade of that oncogenic signal pathway might represent another HDACI mechanism of resensitization of chemoresistant ovarian cancer cells (an antineoplastic effect we previously observed). 6 Similar to EMT, gene set enrichment analysis 35 also demonstrated AR42 gene expression profiles to negatively associate transition (EMT) (Fig.…”

“…3A), which is overexpressed and dysfunctional in CP70 cells (likely contributing to chemotherapy resistance). 36,37 These gene signature here we endeavored to assess global mechanisms (i.e., pathways/ networks) of AR42 cancer cell-specific cytotoxicity, using a "systems biology" approach. 28,29,35 Moreover, with regard to the now well-established role of misexpressed (and frequently epigenetically altered) microRNAs (miRNAs) in ovarian tumorigenesis, 14,[17][18][19]21 we also considered dysregulation of these short, non-protein-coding, translation-regulatory oligonucleotides.…”