Simultaneous Tests of Theaflavin-3,3'-digallate as an Anti-Diabetic Drug in Human Hepatoma G2 Cells and Zebrafish (Danio rerio).

Theaflavin-3,3'-digallate (TF3) is the most important theaflavin monomer in black tea. TF3 was proved to reduce blood glucose level in mice and rats. However, the elaborate anti-diabetic mechanism was not well elucidated. In this work, human hepatoma G2 (HepG2) cells and zebrafish (Danio rerio) were used simultaneously to reveal anti-diabetic effect of TF3. The results showed that TF3 could effectively rise glucose absorption capacity in insulin-resistant HepG2 cells and regulate glucose level in diabetic zebrafish. The hypoglycemic effect was mediated through down-regulating phosphoenolpyruvate carboxykinase and up-regulating glucokinase. More importantly, TF3 could significantly improve ß cells regeneration in diabetic zebrafish at low concentrations (5 µg/mL and 10 µg/mL), which meant TF3 had a strong anti-diabetic effect. Obviously, this work provided the potential benefit of TF3 on hypoglycemic effect, regulating glucose metabolism enzymes, and protecting ß cells. TF3 might be a promising agent for combating diabetes.

Gallic Acid Induces S and G2 Phase Arrest and Apoptosis in Human Ovarian Cancer Cells In Vitro.

Ovarian cancer (OC) is among the top gynecologic cancers in the US with a death tally of 13,940 in the past year alone. Gallic acid (GA) is a natural compound with pharmacological benefits. In this research, the role of GA on cell proliferation, cell apoptosis, cell cycle-related protein expression was explored in OC cell lines OVCAR-3 and A2780/CP70. After 24,48 and 72 h of GA treatment, the IC50 values in OVCAR-3 cells were 22.14 ± 0.45, 20.36 ± 0.18, 15.13 ± 0.53 µM, respectively and in A2780/CP70 cells IC50 values were 33.53 ± 2.64, 27.18 ± 0.22, 22.81 ± 0.56, respectively. Hoechst 33,342 DNA staining and flow cytometry results showed 20 µM GA exposure could significantly accelerate apoptosis in both OC cell lines and the total apoptotic rate increased from 5.34%(control) to 21.42% in OVCAR-3 cells and from 8.01%(control) to 17.69% in A2780/CP70 cells. Western blot analysis revealed that GA stimulated programmed OC cell death via a p53-dependent intrinsic signaling. In addition, GA arrested cell cycle at the S or G2 phase via p53-p21-Cdc2-cyclin B pathway in the same cells. In conclusion, we provide some evidence of the efficacy of GA in ovarian cancer prevention and therapy.

Trichodermin Induces G0/G1 Cell Cycle Arrest by Inhibiting c-Myc in Ovarian Cancer Cells and Tumor Xenograft-Bearing Mice.

Ovarian cancer is a fatal gynecological cancer because of a lack of early diagnosis, which often relapses as chemoresistant. Trichodermin, a trichothecene first isolated from Trichoderma viride, is an inhibitor of eukaryotic protein synthesis. However, whether trichodermin is able to suppress ovarian cancer or not was unclear. In this study, trichodermin (0.5 µM or greater) significantly decreased the proliferation of two ovarian cancer cell lines A2780/CP70 and OVCAR-3. Normal ovarian IOSE 346 cells were much less susceptible to trichodermin than the cancer cell lines. Trichodermin predominantly inhibited ovarian cancer cells by inducing G0/G1 cell cycle arrest rather than apoptosis. Trichodermin decreased the expression of cyclin D1, CDK4, CDK2, retinoblastoma protein, Cdc25A, and c-Myc but showed little effect on the expression of p21Waf1/Cip1, p27Kip1, or p16Ink4a. c-Myc was a key target of trichodermin. Trichodermin regulated the expression of Cdc25A and its downstream proteins via c-Myc. Overexpression of c-Myc attenuated trichodermin's anti-ovarian cancer activity. In addition, trichodermin decelerated tumor growth in BALB/c nude mice, proving its effectiveness in vivo. These findings suggested that trichodermin has the potential to contribute to the treatment of ovarian cancer.

Theasaponin E1 Inhibits Platinum-Resistant Ovarian Cancer Cells through Activating Apoptosis and Suppressing Angiogenesis.

Novel therapeutic strategies for ovarian cancer treatment are in critical need due to the chemoresistance and adverse side effects of platinum-based chemotherapy. Theasaponin E1 (TSE1) is an oleanane-type saponin from Camellia sinensis seeds. Its apoptosis-inducing, cell cycle arresting and antiangiogenesis activities against platinum-resistant ovarian cancer cells were elucidated in vitro and using the chicken chorioallantoic membrane (CAM) assay. The results showed that TSE1 had more potent cell growth inhibitory effects on ovarian cancer OVCAR-3 and A2780/CP70 cells than cisplatin and was lower in cytotoxicity to normal ovarian IOSE-364 cells. TSE1 significantly induced OVCAR-3 cell apoptosis via the intrinsic and extrinsic apoptotic pathways, slightly arresting cell cycle at the G2/M phase, and obviously inhibited OVCAR-3 cell migration and angiogenesis with reducing the protein secretion and expression of vascular endothelial growth factor (VEGF). Western bolt assay showed that Serine/threonine Kinase (Akt) signaling related proteins including Ataxia telangiectasia mutated kinase (ATM), Phosphatase and tensin homolog (PTEN), Akt, Mammalian target of rapamycin (mTOR), Ribosome S6 protein kinase (p70S6K) and e IF4E-binding protein 1(4E-BP1) were regulated, and Hypoxia inducible factor-1α (HIF-1α) protein expression was decreased by TSE1 in OVCAR-3 cells. Moreover, TSE1 treatment potently downregulated protein expression of the Notch ligands including Delta-like protein 4 (Dll4) and Jagged1, and reduced the protein level of the intracellular domain (NICD) of Notch1. Combination treatment of TSE1 with the Notch1 signaling inhibitor tert-butyl (2S)-2-[[(2S)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propanoyl]amino]-2-phenylacetate (DAPT), or the Akt signaling inhibitor wortmannin, showed a stronger inhibition toward HIF-1α activation compared with single compound treatment. Taken together, TSE1 might be a potential candidate compound for improving platinum-resistant ovarian cancer treatment via Dll4/Jagged1-Notch1-Akt-HIF-1α axis.

Saponins Extracted from Tea (Camellia Sinensis) Flowers Induces Autophagy in Ovarian Cancer Cells.

Tea flower saponins (TFS) possess effective anticancer properties. The diversity and complexity of TFS increases the difficulty of their extraction and purification from tea flowers. Here, multiple methods including solvent extraction, microporous resin separation and preparative HPLC separation were used to obtain TFS with a yield of 0.34%. Furthermore, we revealed that TFS induced autophagy-as evidenced by an increase in MDC-positive cell populations and mCherry-LC3B-labeled autolysosomes and an upregulation of LC3II protein levels. 3-MA reversed the decrease in cell viability induced by TFS, showing that TFS induced autophagic cell death. TFS-induced autophagy was not dependent on the Akt/mTOR/p70S6K signaling pathway. TFS-induced autophagy in OVCAR-3 cells was accompanied by ERK pathway activation and reactive oxygen species (ROS) generation. This paper is the first report of TFS-mediated autophagy of ovarian cancer cells. These results provide new insights for future studies of the anti-cancer effects of TFS.

Standardized Saponin Extract from Baiye No.1 Tea (Camellia sinensis) Flowers Induced S Phase Cell Cycle Arrest and Apoptosis via AKT-MDM2-p53 Signaling Pathway in Ovarian Cancer Cells.

Ovarian cancer is considered to be one of the most serious malignant tumors in women. Natural compounds have been considered as important sources in the search for new anti-cancer agents. Saponins are characteristic components of tea (Camellia sinensis) flower and have various biological activities, including anti-tumor effects. In this study, a high purity standardized saponin extract, namely Baiye No.1 tea flower saponin (BTFS), which contained Floratheasaponin A and Floratheasaponin D, were isolated from tea (Camellia sinensis cv. Baiye 1) flowers by macroporous resin and preparative liquid chromatography. Then, the component and purity were detected by UPLC-Q-TOF/MS/MS. This high purity BTFS inhibited the proliferation of A2780/CP70 cancer cells dose-dependently, which is evidenced by the inhibition of cell viability, reduction of colony formation ability, and suppression of PCNA protein expression. Further research found BTFS induced S phase cell cycle arrest by up-regulating p21 proteins expression and down-regulating Cyclin A2, CDK2, and Cdc25A protein expression. Furthermore, BTFS caused DNA damage and activated the ATM-Chk2 signaling pathway to block cell cycle progression. Moreover, BTFS trigged both extrinsic and intrinsic apoptosis-BTFS up-regulated the expression of death receptor pathway-related proteins DR5, Fas, and FADD and increased the ratio of pro-apoptotic/anti-apoptotic proteins of the Bcl-2 family. BTFS-induced apoptosis seems to be related to the AKT-MDM2-p53 signaling pathway. In summary, our results demonstrate that BTFS has the potential to be used as a nutraceutical for the prevention and treatment of ovarian cancer.

Purified Tea (Camellia sinensis (L.) Kuntze) Flower Saponins Induce the p53-Dependent Intrinsic Apoptosis of Cisplatin-Resistant Ovarian Cancer Cells.

Ovarian cancer is currently ranked at fifth in cancer deaths among women. Patients who have undergone cisplatin-based chemotherapy can experience adverse effects or become resistant to treatment, which is a major impediment for ovarian cancer treatment. Natural products from plants have drawn great attention in the fight against cancer recently. In this trial, purified tea (Camellia sinensis (L.) Kuntze) flower saponins (PTFSs), whose main components are Chakasaponin I and Chakasaponin IV, inhibited the growth and proliferation of ovarian cancer cell lines A2780/CP70 and OVCAR-3. Flow cytometry, caspase activity and Western blotting analysis suggested that such inhibitory effects of PTFSs on ovarian cancer cells were attributed to the induction of cell apoptosis through the intrinsic pathway rather than extrinsic pathway. The p53 protein was then confirmed to play an important role in PTFS-induced intrinsic apoptosis, and the levels of its downstream proteins such as caspase families, Bcl-2 families, Apaf-1 and PARP were regulated by PTFS treatment. In addition, the upregulation of p53 expression by PTFSs were at least partly induced by DNA damage through the ATM/Chk2 pathway. The results help us to understand the mechanisms underlying the effects of PTFSs on preventing and treating platinum-resistant ovarian cancer.

Galangin, a Flavonoid from Lesser Galangal, Induced Apoptosis via p53-Dependent Pathway in Ovarian Cancer Cells.

Among women worldwide, ovarian cancer is one of the most dangerous cancers. Patients undergoing platinum-based chemotherapy might get adverse side effects and develop resistance to drugs. In recent years, natural compounds have aroused growing attention in cancer treatment. Galangin inhibited the growth of two cell lines, A2780/CP70 and OVCAR-3, more strongly than the growth of a normal ovarian cell line, IOSE 364. The IC50 values of galangin on proliferation of A2780/CP70, OVCAR-3 and IOSE 364 cells were 42.3, 34.5, and 131.3 µM, respectively. Flow cytometry analysis indicated that galangin preferentially induced apoptosis in both ovarian cancer cells with respect to normal ovarian cells. Galangin treatment increased the level of cleaved caspase-3 and -7 via the p53-dependent intrinsic apoptotic pathway by up-regulating Bax protein and via the p53-dependent extrinsic apoptotic pathway by up-regulating DR5 protein. By down-regulating the level of p53 with 20 µM pifithrin-α (PFT-α), the apoptotic rates of OVCAR-3 cells induced by galangin treatment (40 µM) were significantly decreased from 18.2% to 10.2%, indicating that p53 is a key regulatory protein in galangin-induced apoptosis in ovarian cancer cells. Although galangin up-regulated the expression of p21, it had little effect on the cell cycle of the two ovarian cancer cell lines. Furthermore, the levels of phosphorylated Akt and phosphorylated p70S6K were decreased through galangin treatment, suggesting that the Akt/p70S6K pathways might be involved in the apoptosis. Our results suggested that galangin is selective against cancer cells and can be used for the treatment of platinum-resistant ovarian cancers in humans.

Polyphenols Extracted from Chinese Hickory (Carya cathayensis) Promote Apoptosis and Inhibit Proliferation through the p53-Dependent Intrinsic and HIF-1α-VEGF Pathways in Ovarian Cancer Cells.

Ovarian cancer is the second most common gynecologic cancer with an estimated 13,940 mortalities across the United States in 2020. Natural polyphenols have been shown to double the survival time of some cancer patients due to their anticancer properties. Therefore, the effect of polyphenols extracted from Chinese hickory seed skin Carya cathayensis (CHSP) on ovarian cancer was investigated in the present study. Cell viability results showed that CHSP is more effective in inhibiting ovarian cancer cells than normal ovarian cells, with the IC50 value for inhibition of cell proliferation of Ovarian cancer cells (OVCAR-3) being 10.33 ± 0.166 µg/mL for a 24 h treatment. Flow cytometry results showed that the apoptosis rate was significantly increased to 44.21% after 24 h treatment with 20 µg/mL of CHSP. Western blot analysis showed that CHSP induced apoptosis of ovarian cancer cells through a p53-dependent intrinsic pathway. Compared with control values, levels of VEGF excreted by OVCAR-3 cancer cells were reduced to 7.87% with a 40 µg/mL CHSP treatment. Consistent with our previous reports, CHSP inhibits vascular endothelial growth factor (VEGF) secretion by regulating the HIF-1α-VEGF pathway. In addition, we also found that the inhibitory effect of CHSP on ovarian cancer is related to the up-regulation of Phosphatase and tension homolog (PTEN) and down-regulation of nuclear factor kappa-B (NF-kappa B). These findings provide some evidence of the anti-ovarian cancer properties of CHSP and support the polyphenols as potential candidates for ovarian cancer adjuvant therapy.

SOX2Mediates Carbon Nanotube-Induced Fibrogenesis and Fibroblast Stem Cell Acquisition.

Certain nanosized particles like carbon nanotubes (CNTs) are known to induce pulmonary fibrosis, but the underlying mechanisms are unclear, and efforts to prevent this disease are lacking. Fibroblast-associated stem cells (FSCs) have been suggested as a critical driver of fibrosis induced by CNTs by serving as a renewable source of extracellular matrix-producing cells; however, a detailed understanding of this process remains obscure. Here, we demonstrated that single-walled CNTs induced FSC acquisition and fibrogenic responses in primary human lung fibroblasts. This was indicated by increased expression of stem cell markers (e.g., CD44 and ABCG2) and fibrogenic markers (e.g., collagen and α-SMA) in CNT-exposed cells. These cells also showed increased sphere formation, anoikis resistance, and aldehyde dehydrogenase (ALDH) activities, which are characteristics of stem cells. Mechanistic studies revealed sex-determining region Y-box 2 (SOX2), a self-renewal associated transcription factor, as a key driver of FSC acquisition and fibrogenesis. Upregulation and colocalization of SOX2 and COL1 were found in the fibrotic lung tissues of CNT-exposed mice via oropharyngeal aspiration after 56 days. The knockdown of SOX2 by gene silencing abrogated the fibrogenic and FSC-inducing effects of CNTs. Chromatin immunoprecipitation assays identified SOX2-binding sites on COL1A1 and COL1A2, indicating SOX2 as a transcription factor in collagen synthesis. SOX2 was also found to play a critical role in TGF-ß-induced fibrogenesis through its collagen- and FSC-inducing effects. Since many nanomaterials are known to induce TGF-ß, our findings that SOX2 regulate FSCs and fibrogenesis may have broad implications on the fibrogenic mechanisms and treatment strategies of various nanomaterial-induced fibrotic disorders.

Acquisition of Cancer Stem Cell-like Properties in Human Small Airway Epithelial Cells after a Long-term Exposure to Carbon Nanomaterials.

Cancer stem cells (CSCs) are a key driver of tumor formation and metastasis, but how they are affected by nanomaterials is largely unknown. The present study investigated the effects of different carbon-based nanomaterials (CNMs) on neoplastic and CSC-like transformation of human small airway epithelial cells and determined the underlying mechanisms. Using a physiologically relevant exposure model (long-term/low-dose) with system validation using a human carcinogen, asbestos, we demonstrated that single-walled carbon nanotubes, multi-walled carbon nanotubes, ultrafine carbon black, and crocidolite asbestos induced particle-specific anchorage-independent colony formation, DNA-strand break, and p53 downregulation, indicating genotoxicity and carcinogenic potential of CNMs. The chronic CNM-exposed cells exhibited CSC-like properties as indicated by 3D spheroid formation, anoikis resistance, and CSC markers expression. Mechanistic studies revealed specific self-renewal and epithelial-mesenchymal transition (EMT)-related transcription factors that are involved in the cellular transformation process. Pathway analysis of gene signaling networks supports the role of SOX2 and SNAI1 signaling in CNM-mediated transformation. These findings support the potential carcinogenicity of high aspect ratio CNMs and identified molecular targets and signaling pathways that may contribute to the disease development.

Theaflavin-3,3'-Digallate Suppresses Human Ovarian Carcinoma OVCAR-3 Cells by Regulating the Checkpoint Kinase 2 and p27 kip1 Pathways.

Theaflavin-3,3'-digallate (TF3) is a unique polyphenol in black tea. Epidemiological studies have proved that black tea consumption decreases the incidence rate of ovarian cancer. Our former research demonstrated that TF3 inhibited human ovarian cancer cells. Nevertheless, the roles of checkpoint kinase 2 (Chk2) and p27 kip1 (p27) in TF3-mediated inhibition of human ovarian cancer cells have not yet been investigated. In the current study, TF3 enhanced the phosphorylation of Chk2 to modulate the ratio of pro/anti-apoptotic Bcl-2 family proteins to initiate intrinsic apoptosis in a p53-independent manner and increased the expression of death receptors to activate extrinsic apoptosis in OVCAR-3 human ovarian carcinoma cells. In addition, TF3 up-regulated the expression of p27 to induce G0/G1 cell cycle arrest in OVCAR-3 cells. Our study indicated that Chk2 and p27 were vital anticancer targets of TF3 and provided more evidence that TF3 might be a potent agent to be applied as adjuvant treatment for ovarian cancer.

Synergistic effect of black tea polyphenol, theaflavin-3,3'-digallate with cisplatin against cisplatin resistant human ovarian cancer cells.

Theaflavin-3, 3'-digallate (TF3) is a phenolic compound extracted from black tea. We previously demonstrated that TF3 selectively inhibited ovarian cancer cells. Ovarian cancer has high death rate because of acquired cisplatin resistance. We aimed to investigate the synergistic effect of TF3 and cisplatin (CDDP) against cisplatin resistant ovarian cancer cells. In the present study, combination treatment with TF3 and CDDP showed a synergistic cytotoxic effect in A2780/CP70 and OVCAR3 cells. Combination treatment showed a synergistic pro-apoptotic effect and synergistically induced G1/S phase cell cycle arrest. Synergistic apoptosis was accompanied by regulating protein expression of cleaved caspase 3/7, cytochrome c, Bax and Bcl-2. Combination treatment induced G1/S phase cell cycle arrest via regulating protein expression of cyclin A2, cyclin D1, cyclin E1 and CDK2/4. Combination treatment could synergistically down-regulate Akt phosphorylation in both cell lines. TF3 may be used as an adjuvant for the treatment of advanced ovarian cancer.

Anti-Proliferation Effect of Theasaponin E1 on the ALDH-Positive Ovarian Cancer Stem-Like Cells.

Ovarian cancer has the highest mortality rate of all gynecological malignancies and the five-year death rate of patients has remained high in the past five decades. Recently, with the rise of cancer stem cells (CSCs) theory, an increasing amount of research has suggested that CSCs give rise to tumor recurrence and metastasis. Theasaponin E1 (TSE1), which was isolated from green tea (Camellia sinensis) seeds, has been proposed to be an effective compound for tumor treatment. However, studies on whether TSE1 takes effect through CSCs have rarely been reported. In this paper, ALDH-positive (ALDH+) ovarian cancer stem-like cells from two platinum-resistant ovarian cancer cell lines A2780/CP70 and OVCAR-3 were used to study the anti-proliferation effect of TSE1 on CSCs. The ALDH+ cells showed significantly stronger sphere forming vitality and stronger cell migration capability. In addition, the stemness marker proteins CD44, Oct-4, Nanog, as well as Bcl-2 and MMP-9 expression levels of ALDH+ cells were upregulated compared with the original tumor cells, indicating that they have certain stem cell characteristics. At the same time, the results showed that TSE1 could inhibit cell proliferation and suspension sphere formation in ALDH+ cells. Our data suggests that TSE1 as a natural compound has the potential to reduce human ovarian cancer mortality. However, more research is still needed to find out the molecular mechanism of TSE1-mediated inhibition of ALDH+ cells and possible drug applications on the disease.

Kaempferol Induces G2/M Cell Cycle Arrest via Checkpoint Kinase 2 and Promotes Apoptosis via Death Receptors in Human Ovarian Carcinoma A2780/CP70 Cells.

Kaempferol is a widely distributed dietary flavonoid. Epidemiological studies have demonstrated kaempferol consumption lowers the risk of ovarian cancer. Our previous research proved that kaempferol suppresses human ovarian cancer cells by inhibiting tumor angiogenesis. However, the effects of kaempferol on the cell cycle and extrinsic apoptosis of ovarian cancer cells have not yet been studied. In the present study, we demonstrated that kaempferol induced G2/M cell cycle arrest via the Chk2/Cdc25C/Cdc2 pathway and Chk2/p21/Cdc2 pathway in human ovarian cancer A2780/CP70 cells. Chk2 was not responsible for kaempferol-induced apoptosis and up-regulation of p53. Kaempferol stimulated extrinsic apoptosis via death receptors/FADD/Caspase-8 pathway. Our study suggested that Chk2 and death receptors played important roles in the anticancer activity of kaempferol in A2780/CP70 cells. These findings provide more evidence of the anti-ovarian cancer properties of kaempferol and suggest that kaempferol could be a potential candidate for ovarian cancer adjuvant therapy.

Dietary Compound Proanthocyanidins from Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves inhibit angiogenesis and regulate cell cycle of cisplatin-resistant ovarian cancer cells via targeting Akt pathway.

Ovarian cancer is the leading cause of death from gynecological malignancy and natural products have drawn great attention for cancer treatment. Chinese bayberry leaves proanthocyanidin (BLPs) with epigallocatechin-3-O-gallate (EGCG) as its terminal and major extension units is unusual in the plant kingdom. In the present study, BLPs showed strong growth inhibitory effects on cisplatin-resistant A2780/CP70 cells by inhibiting angiogenesis and inducing G1 cell cycle arrest. BLPs reduced the tube formation in HUVECs and attenuated the wound healing ability in A2780/CP70 cells. BLPs further reduced the level of ROS and targeted Akt/mTOR/p70S6K/4E-BP-1 pathway to reduce the expression of HIF-1α and VEGF, and thus inhibited angiogenesis. Furthermore, BLPs induced G1 cell cycle arrest by reducing the expressions of c-Myc, cyclin D1 and CDK4, which was also in accordance with the flow cytometry analysis. Overall, these results indicated that BLPs could be a valuable resource of natural compounds for cancer treatment.

Flavonoids from Chinese bayberry leaves induced apoptosis and G1 cell cycle arrest via Erk pathway in ovarian cancer cells.

Ovarian cancer is one of the leading causes of death related to the female reproductive system in western countries. Adverse side effects and resistance to platinum based chemotherapy have become the major obstacles for ovarian cancer treatment. Natural products have gained great attention in cancer treatment in recent years. Chinese bayberry leaves flavonoids (BLF) containing rich content of myricitrin (myricetin 3-O-rhamnoside) and a part of quercetrin (quercetin 3-rhamnoside) inhibited the growth of an ovarian cancer cell line A2780/CP70. Such inhibitory effects might be due to the induction of apoptosis and G1 cell cycle arrest. BLF treatment increased the expression of cleaved caspase-3 and -7 and induced apoptosis via a Erk-dependent caspase-9 activation intrinsic apoptotic pathway by up-regulating the pro-apoptotic proteins (Bad and Bax) and down-regulating the anti-apoptotic proteins (Bcl-xL and Bcl-2), which were also in consistency with the results from Hoechst 33342 staining and flow cytometry analysis. Furthermore, by reducing the expression of cyclin D1 and CDK4 and p-Erk, BLF elevated the distribution of G1 phase in cell cycle and thus caused G1 cell cycle arrest. Overall, these results indicated that BLPs could be a valuable resource of natural compound for ovarian cancer treatment.

Theaflavin-3,3'-Digallate Enhances the Inhibitory Effect of Cisplatin by Regulating the Copper Transporter 1 and Glutathione in Human Ovarian Cancer Cells.

Ovarian cancer has the highest fatality rate among the gynecologic cancers. The side effects, high relapse rate, and drug resistance lead to low long-term survival rate (less than 40%) of patients with advanced ovarian cancer. Theaflavin-3,3'-digallate (TF3), a black tea polyphenol, showed less cytotoxicity to normal ovarian cells than ovarian cancer cells. We aimed to investigate whether TF3 could potentiate the inhibitory effect of cisplatin against human ovarian cancer cell lines. In the present study, combined treatment with TF3 and cisplatin showed a synergistic cytotoxicity against A2780/CP70 and OVCAR3 cells. Treatment with TF3 could increase the intracellular accumulation of platinum (Pt) and DNA-Pt adducts and enhanced DNA damage induced by cisplatin in both cells. Treatment with TF3 decreased the glutathione (GSH) levels and upregulated the protein levels of the copper transporter 1 (CTR1) in both cells, which led to the enhanced sensitivity of both ovarian cancer cells to cisplatin. The results imply that TF3 might be used as an adjuvant to potentiate the inhibitory effect of cisplatin against advanced ovarian cancer.

Theaflavin-3, 3'-digallate inhibits ovarian cancer stem cells via suppressing Wnt/ß-Catenin signaling pathway.

Recent evidence indicates that ovarian cancer stem cells (CSCs) are responsible for ovarian cancer recurrence and drug resistance, resulting in the low long-term survival rate of patients with advanced ovarian cancer. We aimed to study the inhibitory effect of theaflavin-3, 3'-digallate (TF3), a black tea polyphenol on ovarian CSCs. Here, we showed that TF3 inhibited the proliferation of A2780/CP70 and OVCAR3 tumorshpere cells by suppressing their cell viability and colony formation capacity. TF3 inhibited the tumorsphere formation capacity of A2780/CP70 and OVCAR3 CSCs in serum-free and non-adherent conditions. TF3 inhibited A2780/CP70 and OVCAR3 CSCs isolated from tumorspheres by decreasing their cell viability and upregulating the protein expression of caspase-3 and -7 in the cells. We also revealed that TF3 inhibited ovarian CSCs through Wnt/ß-catenin signaling pathway. Our results suggested that TF3 could inhibit ovarian CSCs and might be a potential agent for eradicating ovarian cancer.