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Ovarian cancer has the highest rate of death among gynecological malignancy and ranks fifth in cancer deaths among women. Adverse side effects and acquired resistance to conventional chemotherapy based on platinum drive the exploration of other anticancer therapies,thus natural products have drawn greater attention for cancer treatment in recent years. Tea (Camellia sinensis) flower being an abundant agricultural by-product in China and Japan, has been studied for its bio-functional effects. A recent research showed that tea flower saponins (TFS) could induce anti-proliferative effect and cell cycle arrest in human ovarian cancer cells. In the present study, Chakasaponin I, one of the major constituents in TFS, whose main structure is oleanane-type triterpene, showed strong growth inhibitory effects on cisplatin-resistant OVCAR-3 cells at 3 μM by MTS assay. Such inhibitory effects might result from the induction of apoptosis. Western blot assay, Hoechst 33342 staining assay, and flow cytometry analysis were used to examine the effects of Chakasaponin I on apoptosis. The results showed that Chakasaponin I treatment dose-dependently activated the pro-apoptotic proteins (Bad and Bax) and therefore induced apoptosis might by the intrinsic apoptotic pathway. Citation Format: Yi C. Chen. Chakasaponin I from tea (Camellia sinensis) flower induce anti-proliferative effect and apoptosis of cisplatin-resistant ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 716.

Epithelial ovarian cancer is the fifth most common cause of cancer-related death among women in the United States. 3-Hydroxyterphenyllin is a secondary metabolite of Aspergillus fungi. In this study, we evaluated 3-hydroxyterphenyllin as a potential anti-cancer agent using human ovarian cancer cells. The cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in a humidified incubator with 5% CO2. The [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, flow cytometry and western blot analysis were used to confirm that 3-hydroxyterphenyllin exhibited a potent growth inhibitory effect against human ovarian cancer OVCAR-3 and A2780/CP70 cells. 3-hydroxyterphenyllin (2, 4, 8, 12 and 16 μM) reduced the viability of OVCAR-3 and A2780/CP70 cells in a concentration-dependent manner. 3-hydroxyterphenyllin (2, 4 and 8 μM) induced S phase cellular arrest for OVCAR-3 and A2780/CP70 cells by upregulating CyclinB1 and Cdc25A expression and inhibiting Cdk4, CyclinA2 and CyclinE1 expression. These results suggest that 3-hydroxyterphenyllin has the potential to fight ovarian cancer cell growth by preventing progression past the S phase of the cell cycle. Citation Format: Yi C. Chen. 3-Hydroxyterphenyllin induces S phase arrest in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4312.

Theaflavin-3, 3'-digallate (TF3) is a black tea polyphenol produced from polymerization and oxidization of green tea ployphenols epicatechin gallate and (−)-epigallocatechin-3-gallate (EGCG) during fermentation of fresh tea leaves. TF3 has been reported to have anti-cancer properties. However, the effect of TF3 on tumor angiogenesis and the underlying mechanisms are not clear. In the current research, TF3 was verified to inhibit tumor angiogenesis. Compared with EGCG, TF3 was more potent. TF3 inhibited human ovarian carcinoma OVCAR-3 cells induced angiogenesis in human umbilical vein endothelial cell model and in chick chorioallantoic membrane model. TF3 reduced tumor angiogenesis by down-regulating HIF-1α and VEGF. One of the mechanisms was TF3 inactivated Akt/ mTOR/ p70S6K/ 4E-BP1 pathway and Akt/ c-Myc pathway. Besides, TF3 suppressed the cleavage of Notch-1, subsequently decreased the expression of c-Myc, HIF-1α and VEGF, and finally impaired cancer cells induced angiogenesis. Nevertheless, TF3 didn’t have any influence on MAPK pathways. Taken together, these findings suggest that TF3 might serve as a potential anti-angiogenic agent for cancer treatment. Citation Format: Yi C. Chen, Gary O. Rankin. Inhibitory effects of theaflavin-3, 3′-digallate (TF3) on ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 791. doi:10.1158/1538-7445.AM2017-791

Cigarette smoking bears a strong association with the development of lung cancer. Nicotine is the addictive component of cigarettes. Several convergent studies show that nicotine facilitates the growth and angiogenesis of human lung cancers. The biological activity of nicotine is mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand of nAChRs is acetylcholine (ACh). Data from our laboratory and other research groups show that lung cancers express all of the genes for synthesis, transport and degradation of ACh. These include nAChRs, choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), choline transporter (ChT1) and acetylcholinesterase (AChE). Nicotine upregulates the ACh-signaling loop in human lung cancer cells. Therefore, we conjectured that disruption of ACh-signaling pathway should suppress the growth of human cancers. We show that alpha7-nAChR antagonists robustly suppress angiogenesis in human lung and retinal microvascular endothelial cells. The anti-angiogenic activity of alpha7-nAChR antagonists was also observed in chicken chorioallantoic membrane (CAM) and nude mouse models. Similarly, vesamicol, a small molecule antagonist of VAChT, decreases nicotine-induced tumor growth in human NSCLCs. Our studies suggest that the acetylcholine signaling pathway may be have potential applications in the therapy of human lung cancers. Our results are also relevant to lung cancer patients who are exposed to nicotine via secondhand smoke, nicotine patches, gums or electronic cigarettes. Citation Format: Piyali Dasgupta, Kathleen C. Brown, Jamie K. Lau, Aaron M. Dom, Brent A. Thornhill, Clayton M. Crabtree, Theodore R. Witte, W E. Hardman, Cody A. Stover, A B. Carpenter, Yi C. Chen. Disruption of the acetylcholine signaling pathway suppresses the growth and angiogenesis of human lung cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5229. doi:10.1158/1538-7445.AM2015-5229

Ovarian cancer is the 5th leading cause of cancer deaths for women in America. In search for an effective reagent for prevention and treatment of ovarian cancers, we looked into a mycotoxin, chaetoglobosin K (ChK), and investigated its potential of angioprevention in two ovarian cancer cell lines. Cell viability and necrosis were checked with MTS- and LDH-based assays, respectively, and expression of several genes was analyzed by ELISA or Western Blotting. We found this mycotoxin dramatically toxic, sharply reducing cell viability at concentrations of 0.6 to 13 microM, and causing necrosis in both OVCAR-3 and A2780/CP70 cells at 2 microM. However, when applied at low concentrations (0.5 -2 microM), ChK effectively reduced expression of VEGF and HIF-1-alpha proteins, and inhibited phosphorylation of Akt signaling molecules. While further study on ChK is underway, we hypothesize a potential mycotoxin for prevention and treatment of ovarian cancers. Citation Format: Yi C. Chen, Haitao Luo, Zachary Douglas, Shannon Stewart, Zhaoliang Li. Chaetoglobosin K inhibits VEGF expression in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 523. doi:10.1158/1538-7445.AM2013-523

The purpose of this study is to investigate whether and how kaempferol, a dietary flavonoid, induces apoptosis in human ovarian cancer cells. Ovarian cancer cell lines, OVCAR-3, A2780/CP70, and A2780/wt, were treated with kaempferol for 24 hours and analyzed for cell proliferation and cytotoxicity by genomic DNA staining and LDH assay, respectively. Apoptosis of cells were detected with Caspase-Glo 3/7 Assay. Intrinsic apoptotic pathway was further confirmed by pre-treating cancer cells with caspase-9 inhibitor, and tested for caspase 3/7 levels after kaempferol treatment. Protein levels of pro-apoptosis genes including p53, Bad, and Bax, and anti-apoptosis gene, Bcl-XL, were analyzed by western blots. Our data demonstrate that kaempferol inhibits cell proliferation but causes no necrosis in all 3 ovarian cancer cell lines. For apoptosis, caspase 3/7 levels were escalated by kaempferol treatment concentration-dependently and significantly. This effect can be diminished by pre-treatment with caspase-9 inhibitor, indicating an intrinsic apoptosis pathway involved in kaempferol-induced apoptosis in ovarian cancer cells. Western blot analysis revealed that protein levels of anti-apoptosis gene, Bcl-xL were decreased in ovarian cancer cells, while pro-apoptotic genes, p53, Bad, and Bax, were up-regulated by kaempferol treatment. In conclusion, kaempferol induces apoptosis in ovarian cancer cells through regulating expression of both pro-apoptotic and anti-apoptotic genes within the intrinsic apoptosis pathway. As a natural flavonoid wildly distributed in fruits and vegetables, kaempferol is a good candidate for chemoprevention of ovarian cancers in humans. Further studies in animal models and clinical trials are warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 189. doi:10.1158/1538-7445.AM2011-189

This study was designed to investigate kaempferol's effects on VEGF expression and angiogenesis in ovarian cancer cells and the underlying mechanisms/pathways responsible for these effects. Kaempferol's effects on VEGF expression in ovarian cancer cells, OVCAR-3 and A2780/CP70, were studied with ELISA and a VEGF promoter reporter assay. In-vitro and in-vivo angiogenesis were studied with human umbilical vein endothelial cells and chicken embryo chorioallantoic membranes, respectively. Expression or phosphorylation of pertinent genes in ovarian cancer cells treated with kaempferol (0-160 µM) was examined with RT-qPCR, western blot, or ELISA as appropriate. To investigate kaempferol's effects on VEGF expression, the expression of certain genes was either enhanced by transfection of plasmid DNA or knocked down by transfection of siRNA, and the resultant effects evaluated by using a VEGF promoter reporter assay or RT-qPCR. Our study found that kaempferol is effective in inhibiting VEGF expression, in-vitro and in-vivo angiogenesis, and in-vivo tumorigenesis at physiologically relevant concentrations (e.g. 40 µM). We further looked into mechanisms/pathways for these effects, and confirmed a role for Akt and HIF-1α in kaempferol's inhibition on VEGF expression. We discovered that a new HIF-1α-independent pathway is also involved in VEGF regulation. Our results showed that kaempferol executes its effects on VEGF expression through regulating ERRα but not PPARGC1A in OVCAR-3 and A2780/CP70 cells. We also identified cMyc/p21 as a novel pathway for kaempferol's inhibitory effects on VEGF expression in ovarian cancer cells. Our study found that kaempferol is effective for angio-prevention in ovarian cancer cells, and new information was obtained on the mechanisms/pathways for kaempferol's effects. As a dietary flavonoid, kaempferol is a good candidate for angio-prevention and primary prevention of ovarian cancers, and it deserves further investigation in animal studies and human trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 340.