Epigallocatechin gallate sensitizes cisplatin-resistant oral cancer CAR cell apoptosis and autophagy through stimulating AKT/STAT3 pathway and suppressing multidrug resistance 1 signaling.

Epigallocatechin gallate (EGCG) is a green tea polyphenol that presents anticancer activities in multiple cancer cells, but no available report was addressed for the underling molecular mechanism of cytotoxic impacts on drug-resistant oral squamous cell carcinoma cells. In the present study, the inhibitory effects of EGCG were experienced on cisplatin-resistant oral cancer CAR cells. EGCG inhibited cell viability in a time- and concentration-dependent manner by a sulforhodamine B (SRB) assay. EGCG induced CAR cell apoptosis and autophagy by 4',6-diamidino-2-phenylindole (DAPI) dye, acridine orange (AO) staining and green fluorescent protein (GFP)-tagged LC3B assay, respectively. EGCG also significantly enhanced caspase-9 and caspase-3 activities by caspase activity assay. EGCG markedly increased the protein levels of Bax, cleaved caspase-9, cleaved caspase-3, Atg5, Atg7, Atg12, Beclin-1, and LC3B-II, as well as significantly decreased the expression of Bcl-2, phosphorylated AKT (Ser473) and phosphorylation of STAT3 on Tyr705 by western blotting in CAR cells. Importantly, the protein and gene expression of multidrug resistance 1 (MDR1) were dose-dependently inhibited by EGCG. Overall, downregulation of MDR1 levels and alterations of AKT/STAT3 signaling contributed to EGCG-induced apoptosis and autophagy in CAR cells. Based on these results, EGCG has the potential for therapeutic effect on oral cancer and may be useful for long-term oral cancer prevention in the future. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 845-855, 2017.

Yuan CH ，Horng CT ，Lee CF ，Chiang NN ，Tsai FJ ，Lu CC ，Chiang JH ，Hsu YM ，Yang JS ，Chen FA ... -  《-》

Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells: A key role of AMPK and Akt/mTOR signaling.

Chang CH ，Lee CY ，Lu CC ，Tsai FJ ，Hsu YM ，Tsao JW ，Juan YN ，Chiu HY ，Yang JS ，Wang CC ... -  《-》

Epigallocatechin-3-gallate promotes apoptosis and reversal of multidrug resistance in esophageal cancer cells.

Evidence for demonstrating the role of the green tea component epigallocatechin-3-gallate (EGCG) in esophageal squamous cell carcinoma cells is limited. In this study, we investigated apoptosis induced by EGCG and the underlying molecular mechanisms in human esophageal squamous cell carcinoma cells. The growth-inhibitory effects of EGCG on esophageal cancer cell (Eca109 and Ec9706) were detected by MTT. Using flow cytometry, we determined the cellular apoptosis, bcl-2, bax and caspase-3 protein expression in Eca109 and Ec9706 cells following treatment with EGCG for 24h. After treatment of Eca109/ABCG2 (an esophageal cancer multidrug resistance cell line) cells with adriamycin (ADM) combined with EGCG for 24h, the cellular apoptosis, mitochondrial membrane potential, ADM concentration in cells and ABCG2 protein expression were detected by flow cytometry. EGCG inhibited the growth of Eca109 and Ec9706 cells in a dose- and time- dependent manner. EGCG induced apoptosis, decreased the bcl-2 protein expression and increased the expression of bax and caspase-3 protein. The rate of apoptosis and ADM concentration in the Eca109/ABCG2 cells following treatment with ADM and EGCG were higher than that with ADM treatment alone, although the mitochondrial membrane potential was significantly lower (P<0.01). EGCG reduced the ABCG2 expression of Eca109/ABCG2 cells. Our data indicated that EGCG inhibited cell growth and induced esophageal cancer cell apoptosis. It reduced the bcl-2 protein expression and increased the bax and caspase-3 protein expression. EGCG reversed multi-drug resistance by reducing ABCG2 expression and increasing the anticancer drug concentration in cancer cells.

Liu L ，Ju Y ，Wang J ，Zhou R ... -  《-》

Cinnamaldehyde derivative (CB-PIC) sensitizes chemo-resistant cancer cells to drug-induced apoptosis via suppression of MDR1 and its upstream STAT3 and AKT signalling.

Our group reported that cinnamaldehyde derivative, (E)-4-((2-(3-oxopop-1-enyl)phenoxy)methyl)pyridinium malonic acid (CB-PIC) induced apoptosis in hypoxic SW620 colorectal cancer cells via activation of AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase (ERK). Herein, sensitizing effect of CB-PIC was investigated in resistant cancer cells such as paclitaxel (PT) resistant lung cancer cells (H460/PT), and Adriamycin (Adr) resistant breast cancer (MCF7/Adr) and colon cancer (HCT15/cos) cells. Various drug resistant cell lines were treated with CB-PIC, and the signalling pathway and functional assay were explored by Western blot, Rhodamine assay, FACS, RT-PCR and MTT assay. We found that CB-PIC effectively exerted cytotoxicity, increased sub G1 population and the cleaved form of poly (ADP-ribose) polymerase (PARP) and caspase 9 in drug resistant cancer cells. Furthermore, CB-PIC sensitized resistant cancer cells to adriamycin via downregulation of survival proteins such as survivin, Bcl-xL and Bcl-2, along with MDR1 suppression leading to accumulation of drug in the intracellular region. Of note, CB-PIC transcriptionally decreased MDR1 expression via suppression of STAT3 and AKT signalling in three resistant cancer cells with highly expressed P-glycoprotein. Nonetheless, CB-PIC did not affect transport activity of P-glycoprotein in a short time efflux assay, while epigallocatechin gallate (EGCG) accumulated Rhodamine 123 into intracellular region of cell by direct inhibition of MDR1 transport activity. These data demonstrate that CB-PIC suppresses the P-glycoprotein expression through inhibition of STAT3 and AKT signalling to overcome drug resistance in chemo-resistant cancer cells as a potent chemotherapeutic sensitizer.

Yun M ，Lee D ，Park MN ，Kim EO ，Sohn EJ ，Kwon BM ，Kim SH ... -  《-》

(-)-Epigallocatechin gallate induces Fas/CD95-mediated apoptosis through inhibiting constitutive and IL-6-induced JAK/STAT3 signaling in head and neck squamous cell carcinoma cells.

Lin HY ，Hou SC ，Chen SC ，Kao MC ，Yu CC ，Funayama S ，Ho CT ，Way TD ... -  《-》