The Experts below are selected from a list of 204 Experts worldwide ranked by ideXlab platform
Karl Wah Keung Tsim - One of the best experts on this subject based on the ideXlab platform.
-
Ginkgetin derived from ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis mediated disruption of the nrf2 ho 1 axis in egfr wild type non small cell lung cancer
Phytomedicine, 2021Co-Authors: Jian Shu Lou, Karl Wah Keung Tsim, Liping Zhao, Zhi Hui Huang, Xia Yin Chen, William Chishing Tai, Yi Tao Chen, Tian XieAbstract:Abstract Background Cisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small-cell lung cancer (NSCLC). A recent study indicated that DDP could slightly induce non-apoptotic cell death ferroptosis, and the cytotoxicity was promoted by ferroptosis inducer. The agents enhancing the ferroptosis may therefore increase the anticancer effect of DDP. Several lines of evidence supporting the use of phytochemicals in NSCLC therapy. Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves, showed anticancer effects on NSCLC by triggering autophagy. Ferroptosis can be triggered by autophagy, which regulates redox homeostasis. Thus, we aimed to elucidate the possible role of ferroptosis involved in the synergistic effect of Ginkgetin and DDP in cancer therapy. Methods The promotion of DDP-induced anticancer effects by Ginkgetin was examined via a cytotoxicity assay and western blot. Ferroptosis triggered by Ginkgetin in DDP-treated NSCLC was observed via a lipid peroxidation assay, a labile iron pool assay, western blot, and qPCR. With ferroptosis blocking, the contribution of ferroptosis to Ginkgetin + DDP-induced cytotoxicity, the Nrf2/HO-1 axis, and apoptosis were determined via a luciferase assay, immunostaining, chromatin immunoprecipitation (CHIP), and flow cytometry. The role of ferroptosis in Ginkgetin + DDP-treated NSCLC cells was illustrated by the application of ferroptosis inhibitors, which was further demonstrated in a xenograft nude mouse model. Results Ginkgetin synergized with DDP to increase cytotoxicity in NSCLC cells, which was concomitant with increased labile iron pool and lipid peroxidation. Both these processes were key characteristics of ferroptosis. The induction of ferroptosis mediated by Ginkgetin was further confirmed by the decreased expression of SLC7A11 and GPX4, and a decreased GSH/GSSG ratio. Simultaneously, Ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured NSCLC cells. Furthermore, blocking ferroptosis reversed the Ginkgetin-induced inactivation of Nrf2/HO-1 as well as the elevation of ROS formation, MMP loss, and apoptosis in DDP-treated NSCLC cells. Conclusion This study is the first to report that Ginkgetin derived from Ginkgo biloba leaves promotes DDP-induced anticancer effects, which can be due to the induction of ferroptosis.
-
synergy of Ginkgetin and resveratrol in suppressing vegf induced angiogenesis a therapy in treating colorectal cancer
Cancers, 2019Co-Authors: Gallant K L Chan, Ran Duan, Huaiyou Wang, Xiangpeng Kong, Tina Tingxia Dong, Karl Wah Keung TsimAbstract:Ginkgetin, a biflavone from Ginkgo biloba leaf, and resveratrol, a polyphenol found in grape and wine, are two phytochemicals being identified for its binding to vascular endothelial growth factor (VEGF): the binding, therefore, resulted in the alteration of the physiological roles of VEGF-mediated angiogenesis. The bindings of Ginkgetin and resveratrol were proposed on different sites of VEGF, but both of them suppressed the angiogenic properties of VEGF. The suppressive activities of Ginkgetin and resveratrol in VEGF-mediated angiogenesis were supported by several lines of evidence including (i) inhibiting the formation of sub-intestinal vessel in zebrafish embryos and microvascular sprouting in rat aortic ring; and (ii) suppressing the phosphorylations of VEGFR2, Akt, eNOS, and Erk as well as expressions of matrix metalloproteinases (MMPs), MMP-2, and MMP-9 in human umbilical vein endothelial cells (HUVECs). Here, we showed the synergy of Ginkgetin and resveratrol in suppressing the VEGF-induced endothelial cell proliferation, migration, invasion, and tube formation. The synergy of Ginkgetin and resveratrol was further illustrated in HT-29 colon cancer xenograft nude mice. Ginkgetin and resveratrol, when applied together, exerted a synergistic anti-tumor effect of 5-fluorouracil with decreasing microvessel density of tumors. In parallel, the combination of Ginkgetin and resveratrol synergistically relieved the 5-fluorouracil-induced inflammatory response by suppressing expressions of COX-2 and inflammatory cytokines. Thus, the anti-angiogenic roles of Ginkgetin and/or resveratrol could provide effective therapeutic strategy in cancer, similar to that of Avastin, in suppressing the VEGF-mediated angiogenesis during cancer development.
-
Ginkgetin induces autophagic cell death through p62 sqstm1 mediated autolysosome formation and redox setting in non small cell lung cancer
Oncotarget, 2017Co-Authors: Jian Shu Lou, Gallant K L Chan, Huaiyou Wang, Jin Yan, Chauwing Wong, Zhongyu Zhou, Ping Yao, Tina T X Dong, Karl Wah Keung TsimAbstract:// Jian-Shu Lou 1, 2 , Wen-Chuan Bi 1, 2 , Gallant K.L. Chan 1, 2 , Yan Jin 1, 2 , Chau-Wing Wong 2 , Zhong-Yu Zhou 2 , Huai-You Wang 1, 2 , Ping Yao 2 , Tina T.X. Dong 1, 2 and Karl W.K. Tsim 1, 2 1 Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China 2 Division of Life Science, Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China Correspondence to: Karl W.K. Tsim, email: botsim@ust.hk Keywords: autophagy, natural compounds, non-small cell lung cancer, p62, mTORC1 Received: July 12, 2017 Accepted: August 27, 2017 Published: October 16, 2017 ABSTRACT Promoting cell death by autophagy could be a novel treatment for cancer. The major player in autophagy, p62, serves as a good therapeutic target. Ginkgetin, a biflavonoid from Ginkgo biloba leaves, exhibited promising anticancer activity in non-small cell lung cancer cell lines, with an IC50 lower than that of cisplatin. This anticancer effect of Ginkgetin was illustrated in a xenograft nude mouse model. Ginkgetin induced autophagic cell death in A549 cells, and this effect was markedly reversed by chemical and genetic approaches. Ginkgetin showed potential binding affinity to p62. Upregulation of p62 through chemical and genetic means decreased cell death, lysosome acidification, and autophagosome formation, which consequently disrupted autolysosome formation. In addition, the decreased autophagy induced by p62 overexpression increased Nrf2/ARE activity and the oxygen consumption rate and decreased on formation of reactive oxygen species. These phenomena were exhibited in a reciprocal manner when p62 was knocked down. Thus, p62 may be a potential target in Ginkgetin-induced autophagic cell death, and Ginkgetin could be developed as a novel anticancer drug.
-
Abstract 3325: Ginkgetin, a biflavonoid derived from leaves ofGinkgo biloba, induces autophagic cell death in non-small cell lung cancer via p62
Cancer Research, 2017Co-Authors: Cathy W C Bi, Tina Dong, Gallant K L Chan, Karl Wah Keung TsimAbstract:Chemotherapeutic drugs in the treatment of non-small-cell lung carcinoma (NSCLC) are usually mediated by induction of apoptosis; this usually results in drug resistant during the therapy. Many compounds from natural resource have been shown to trigger autophagy in promoting cell death, and therefore which could be a novel treatment for cancer. Ginkgetin, a biflavonoid from Ginkgo biloba leaves (Ginkgoaceae), was shown its anticancer effects recently. The leaf of G. biloba is being recorded as a safe herbal drug in Pharmacopoeia from China and Europe. Here, the possible development of Ginkgetin as an anticancer drug was demonstrated. Ginkgetin induced the death in A549 (NSCLC) with an IC50 lower than that of cisplatin. This anticancer effect of Ginkgetin was also illustrated in NSCLC xenograft nude mice model. Transmission electronic microscope revealed that Ginkgetin-induced autophagy was the main cause of cell death. Autophagy inhibitors, 3-methyladenine and chloroquine but not apoptosis inhibitor Z-VAD-FMK, rescued Ginkgetin-induced cell death. Reciprocally, the induction of autophagy by rapamycin promoted Ginkgetin-induced cell death, as well as the formation of p62-TRAF6-mTOR. During autophagy, p62 is hypothesized to be a target of Ginkgetin-induced autophagic cell death. This notion is supported by several lines of evidence. The application of Ginkgetin blocked fully the expression of p62 in cultured A549, and in contrast the over expression of p62 reduced Ginkgetin-induced autophagy and cell death concomitantly with the decline on autophagosome formation. In parallel, the modulation on p62 expression could regulate Nrf2 activity and ROS level in the presence of Ginkgetin. Thus, autophagy could act as an inducer in Ginkgetin-induced cell death, and p62 was proposed to be a possible target during this process. Here, Ginkgetin exhibited promising anticancer effect in NSCLC via autophagy, a signaling very different to orthodox chemotherapeutic drug cisplatin. Besides, Ginkgetin is a phytochemical from G. biloba that is considered as a safe herbal supplement, and no obvious toxicity was observed in xenograft nude mice. Therefore, Ginkgetin is proposed to be a potential compound for the development of novel anticancer drug. Acknowledgements: This study was supported by Hong Kong Research Grants Council Theme-based Research Scheme (T13-607/12R), GRF (663012, 662713, M-HKUST604/13), TUYF15SC01 and Foundation of The Awareness of Nature (TAON12SC01) to Karl Tsim. Citation Format: Jian Shu Lou, Cathy Bi, Gallant Chan, Tina Dong, Karl Tsim. Ginkgetin, a biflavonoid derived from leaves of Ginkgo biloba, induces autophagic cell death in non-small cell lung cancer via p62 [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 3325. doi:10.1158/1538-7445.AM2017-3325
Hyun Pyo Kim - One of the best experts on this subject based on the ideXlab platform.
-
effects of anti inflammatory biflavonoid Ginkgetin on chronic skin inflammation
Biological & Pharmaceutical Bulletin, 2006Co-Authors: Hyun Lim, Sam-sik Kang, Hyeun Wook Chang, Kun Ho Son, Hyun Pyo KimAbstract:Ginkgetin, a biflavonoid from Ginkgo biloba leaves (Ginkgoaceae), was previously demonstrated to inhibit phospholipase A2 and to suppress proinflammatory gene expression such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase. In this study, the effects of Ginkgetin were examined on an animal model of chronic skin inflammation and proinflammatory gene expression. When topically applied to ICR mouse ear, Ginkgetin (20-80 microg/ear/treatment) inhibited ear edema (22.8-30.5%) and prostaglandin E2 production (30.2-31.1%) induced by multiple treatment of 12-O-tetradecanoylphorbol-13-acetate (TPA) for 7 consecutive days. By histological comparison, Ginkgetin was also found to reduce epidermal hyperplasia. The expression of proinflammatory gene, interleukin-1beta, was suppressed by Ginkgetin. From the results, it is suggested that Ginkgetin may be beneficial against chronic skin inflammatory disorders like atopic dermatitis.
-
Ginkgetin a biflavone from ginko biloba leaves inhibits cyclooxygenases 2 and 5 lipoxygenase in mouse bone marrow derived mast cells
Biological & Pharmaceutical Bulletin, 2005Co-Authors: Jong Keun Son, Sam-sik Kang, Kun Ho Son, Hyun Pyo Kim, Min Jung Son, Eunkyung Lee, Tae Chul Moon, Cheorl Ho Kim, Hyeun Wook ChangAbstract:Ginkgetin, a biflavone from Ginkgo biloba leaves, was previously reported to be a phospholipase A2 inhibitor and this compound showed the potent antiarthritic activity in rat adjuvant-induced arthritis as well as analgesic activity. This investigation was carried out to find effects on cyclooxygenase-2 (COX-2) in vitro effect. Ginkgetin inhibits COX-2 dependent phases of prostaglandin D2 (PGD2) generation in bone marrow-derived mast cells (BMMC) in a concentration-dependent manner with IC50 values of 0.75 μM. Western blotting probed with specific anti-COX-2 antibodies showed that the decrease in quantity of the PGD2 product was accompanied by a decrease in the COX-2 protein level. In addition, this compound consistently inhibited the production of leukotriene C4 (LTC4) in a dose dependent manner, with an IC50 value of 0.33 μM. These results demonstrate that Ginkgetin has a dual cyclooxygenase-2/5-lipoxygenase inhibitory activity. Furthermore, this compound also inhibited degranulation reaction in a dose dependent manner, with an IC50 value of 6.52 μM. Therefore, this compound might provide a basis for novel anti-inflammatory agents.
-
effects of Ginkgetin from ginkgo biloba leaves on cyclooxygenases and in vivo skin inflammation
Planta Medica, 2002Co-Authors: Wiejong Kwak, Sam-sik Kang, Hyeun Wook Chang, Kun Ho Son, Chang Kyun Han, Byoung Kyu Park, Hyun Pyo KimAbstract:Ginkgetin, a biflavone from Ginkgo biloba leaves, was previously reported to be a phospholipase A2 inhibitor and this compound showed the potent antiarthritic activity in rat adjuvant-induced arthritis as well as analgesic activity. This investigation was carried out to find effects on cyclooxygenase (COX)-1 and -2 including an in vivo effect. Ginkgetin (1 - 10 microM) and the biflavonoid mixture (10 - 50 microg/ml), mainly a 1 : 1 mixture of Ginkgetin and isoGinkgetin, from G. biloba leaves, inhibited production of prostaglandin E2 from lipopolysaccharide-induced RAW 264.7 cells. This inhibition was mediated, at least in part, by down-regulation of COX-2 expression, but not by direct inhibition of COX-1 or COX-2 activity. Down-regulation of COX-2 by Ginkgetin was also proved in the dorsal skin of ICR mouse treated by 12-O-tetradecanoylphorbol 13-acetate (TPA). At total doses of 1,000 microg/site on the dorsal skin (15 mm x 15 mm), Ginkgetin inhibited prostaglandin E2 production by 65.6 % along with a marked suppression of COX-2 induction. In addition, Ginkgetin and the biflavonoid mixture (100 - 1,000 microg/ear) dose-dependently inhibited skin inflammation of croton oil induced ear edema in mice by topical application. The present study suggests that Ginkgetin from G. biloba leaves down-regulates COX-2 induction in vivo and this down-regulating potential is associated with an anti-inflammatory activity against skin inflammatory responses.
-
inhibition of rat adjuvant induced arthritis by Ginkgetin a biflavone from ginkgo biloba leaves
Planta Medica, 1999Co-Authors: Hee Kee Kim, Sam-sik Kang, Hyeun Wook Chang, Kun Ho Son, Hyun Pyo KimAbstract:Ginkgetin, a biflavone isolated from Ginkgo biloba leaves, was previously reported as an inhibitor of group II phospholipase A2. In this study, Ginkgetin was evaluated for in vivo antiarthritic and analgesic activities. Ginkgetin (10-20 mg/kg/day) strongly reduced arthritic inflammation in an animal model of rat adjuvant-induced arthritis (86% inhibition at 16 days at a dose of 20 mg/kg/day) via intraperitoneal injection, while prednisolone (5 mg/kg/day) showed 79% reduction. Histological examination of the knee joints confirmed our findings. When analgesic activity was measured, Ginkgetin showed a dose-dependent inhibition in an animal model of acetic acid-induced writhing. ED50 values for Ginkgetin and indomethacin were 8.9 and 3.8 mg/kg, respectively. All these results indicate that Ginkgetin may be a potential antiarthritic agent having analgesic activity.
Qiang Wang - One of the best experts on this subject based on the ideXlab platform.
-
optimization of process parameters of extraction of amentoflavone quercetin and Ginkgetin from taxus chinensis using supercritical co2 plus co solvent
Molecules, 2014Co-Authors: Xiao Ruan, Xianxian Li, Huan Zhang, Qiang WangAbstract:The effects of extraction time, temperature, pressure and different concentration of ethanol and their interactions on the yields of amentoflavone, quercetin and Ginkgetin extracted from Taxus chinensis by supercritical CO2 were investigated by using a central composite design (CCD). An CCD experimental design with four factors and five levels was used to optimize the extraction parameters. Ultra performance liquid chromatography (UPLC) was used to analyze the content of the tree components in the extracts. Experimental results show that the main effects of factors and their interactions are significant on the yields (p < 0.05). The optimal extraction conditions were established for the three compounds: yield of 4.47 mg/g for amentoflavone at 48 °C, 25 MPa, 2.02 h and 78.5% ethanol, 3.73 mg/g for quercetin at 46 °C, 24 MPa, 2.3 h, 82% ethanol and 3.47 mg/g for Ginkgetin at 48 °C, 20 MPa, 2.38 h, 82% ethanol, respectively.
-
optimization of process parameters of extraction of amentoflavone quercetin and Ginkgetin from taxus chinensis using supercritical co2 plus co solvent
Molecules, 2014Co-Authors: Xiao Ruan, Xianxian Li, Huan Zhang, Qiang WangAbstract:The effects of extraction time, temperature, pressure and different concentration of ethanol and their interactions on the yields of amentoflavone, quercetin and Ginkgetin extracted from Taxus chinensis by supercritical CO2 were investigated by using a central composite design (CCD). An CCD experimental design with four factors and five levels was used to optimize the extraction parameters. Ultra performance liquid chromatography (UPLC) was used to analyze the content of the tree components in the extracts. Experimental results show that the main effects of factors and their interactions are significant on the yields (p < 0.05). The optimal extraction conditions were established for the three compounds: yield of 4.47 mg/g for amentoflavone at 48 °C, 25 MPa, 2.02 h and 78.5% ethanol, 3.73 mg/g for quercetin at 46 °C, 24 MPa, 2.3 h, 82% ethanol and 3.47 mg/g for Ginkgetin at 48 °C, 20 MPa, 2.38 h, 82% ethanol, respectively.
Gallant K L Chan - One of the best experts on this subject based on the ideXlab platform.
-
synergy of Ginkgetin and resveratrol in suppressing vegf induced angiogenesis a therapy in treating colorectal cancer
Cancers, 2019Co-Authors: Gallant K L Chan, Ran Duan, Huaiyou Wang, Xiangpeng Kong, Tina Tingxia Dong, Karl Wah Keung TsimAbstract:Ginkgetin, a biflavone from Ginkgo biloba leaf, and resveratrol, a polyphenol found in grape and wine, are two phytochemicals being identified for its binding to vascular endothelial growth factor (VEGF): the binding, therefore, resulted in the alteration of the physiological roles of VEGF-mediated angiogenesis. The bindings of Ginkgetin and resveratrol were proposed on different sites of VEGF, but both of them suppressed the angiogenic properties of VEGF. The suppressive activities of Ginkgetin and resveratrol in VEGF-mediated angiogenesis were supported by several lines of evidence including (i) inhibiting the formation of sub-intestinal vessel in zebrafish embryos and microvascular sprouting in rat aortic ring; and (ii) suppressing the phosphorylations of VEGFR2, Akt, eNOS, and Erk as well as expressions of matrix metalloproteinases (MMPs), MMP-2, and MMP-9 in human umbilical vein endothelial cells (HUVECs). Here, we showed the synergy of Ginkgetin and resveratrol in suppressing the VEGF-induced endothelial cell proliferation, migration, invasion, and tube formation. The synergy of Ginkgetin and resveratrol was further illustrated in HT-29 colon cancer xenograft nude mice. Ginkgetin and resveratrol, when applied together, exerted a synergistic anti-tumor effect of 5-fluorouracil with decreasing microvessel density of tumors. In parallel, the combination of Ginkgetin and resveratrol synergistically relieved the 5-fluorouracil-induced inflammatory response by suppressing expressions of COX-2 and inflammatory cytokines. Thus, the anti-angiogenic roles of Ginkgetin and/or resveratrol could provide effective therapeutic strategy in cancer, similar to that of Avastin, in suppressing the VEGF-mediated angiogenesis during cancer development.
-
Ginkgetin induces autophagic cell death through p62 sqstm1 mediated autolysosome formation and redox setting in non small cell lung cancer
Oncotarget, 2017Co-Authors: Jian Shu Lou, Gallant K L Chan, Huaiyou Wang, Jin Yan, Chauwing Wong, Zhongyu Zhou, Ping Yao, Tina T X Dong, Karl Wah Keung TsimAbstract:// Jian-Shu Lou 1, 2 , Wen-Chuan Bi 1, 2 , Gallant K.L. Chan 1, 2 , Yan Jin 1, 2 , Chau-Wing Wong 2 , Zhong-Yu Zhou 2 , Huai-You Wang 1, 2 , Ping Yao 2 , Tina T.X. Dong 1, 2 and Karl W.K. Tsim 1, 2 1 Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China 2 Division of Life Science, Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China Correspondence to: Karl W.K. Tsim, email: botsim@ust.hk Keywords: autophagy, natural compounds, non-small cell lung cancer, p62, mTORC1 Received: July 12, 2017 Accepted: August 27, 2017 Published: October 16, 2017 ABSTRACT Promoting cell death by autophagy could be a novel treatment for cancer. The major player in autophagy, p62, serves as a good therapeutic target. Ginkgetin, a biflavonoid from Ginkgo biloba leaves, exhibited promising anticancer activity in non-small cell lung cancer cell lines, with an IC50 lower than that of cisplatin. This anticancer effect of Ginkgetin was illustrated in a xenograft nude mouse model. Ginkgetin induced autophagic cell death in A549 cells, and this effect was markedly reversed by chemical and genetic approaches. Ginkgetin showed potential binding affinity to p62. Upregulation of p62 through chemical and genetic means decreased cell death, lysosome acidification, and autophagosome formation, which consequently disrupted autolysosome formation. In addition, the decreased autophagy induced by p62 overexpression increased Nrf2/ARE activity and the oxygen consumption rate and decreased on formation of reactive oxygen species. These phenomena were exhibited in a reciprocal manner when p62 was knocked down. Thus, p62 may be a potential target in Ginkgetin-induced autophagic cell death, and Ginkgetin could be developed as a novel anticancer drug.
-
Abstract 3325: Ginkgetin, a biflavonoid derived from leaves ofGinkgo biloba, induces autophagic cell death in non-small cell lung cancer via p62
Cancer Research, 2017Co-Authors: Cathy W C Bi, Tina Dong, Gallant K L Chan, Karl Wah Keung TsimAbstract:Chemotherapeutic drugs in the treatment of non-small-cell lung carcinoma (NSCLC) are usually mediated by induction of apoptosis; this usually results in drug resistant during the therapy. Many compounds from natural resource have been shown to trigger autophagy in promoting cell death, and therefore which could be a novel treatment for cancer. Ginkgetin, a biflavonoid from Ginkgo biloba leaves (Ginkgoaceae), was shown its anticancer effects recently. The leaf of G. biloba is being recorded as a safe herbal drug in Pharmacopoeia from China and Europe. Here, the possible development of Ginkgetin as an anticancer drug was demonstrated. Ginkgetin induced the death in A549 (NSCLC) with an IC50 lower than that of cisplatin. This anticancer effect of Ginkgetin was also illustrated in NSCLC xenograft nude mice model. Transmission electronic microscope revealed that Ginkgetin-induced autophagy was the main cause of cell death. Autophagy inhibitors, 3-methyladenine and chloroquine but not apoptosis inhibitor Z-VAD-FMK, rescued Ginkgetin-induced cell death. Reciprocally, the induction of autophagy by rapamycin promoted Ginkgetin-induced cell death, as well as the formation of p62-TRAF6-mTOR. During autophagy, p62 is hypothesized to be a target of Ginkgetin-induced autophagic cell death. This notion is supported by several lines of evidence. The application of Ginkgetin blocked fully the expression of p62 in cultured A549, and in contrast the over expression of p62 reduced Ginkgetin-induced autophagy and cell death concomitantly with the decline on autophagosome formation. In parallel, the modulation on p62 expression could regulate Nrf2 activity and ROS level in the presence of Ginkgetin. Thus, autophagy could act as an inducer in Ginkgetin-induced cell death, and p62 was proposed to be a possible target during this process. Here, Ginkgetin exhibited promising anticancer effect in NSCLC via autophagy, a signaling very different to orthodox chemotherapeutic drug cisplatin. Besides, Ginkgetin is a phytochemical from G. biloba that is considered as a safe herbal supplement, and no obvious toxicity was observed in xenograft nude mice. Therefore, Ginkgetin is proposed to be a potential compound for the development of novel anticancer drug. Acknowledgements: This study was supported by Hong Kong Research Grants Council Theme-based Research Scheme (T13-607/12R), GRF (663012, 662713, M-HKUST604/13), TUYF15SC01 and Foundation of The Awareness of Nature (TAON12SC01) to Karl Tsim. Citation Format: Jian Shu Lou, Cathy Bi, Gallant Chan, Tina Dong, Karl Tsim. Ginkgetin, a biflavonoid derived from leaves of Ginkgo biloba, induces autophagic cell death in non-small cell lung cancer via p62 [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 3325. doi:10.1158/1538-7445.AM2017-3325
Jian Shu Lou - One of the best experts on this subject based on the ideXlab platform.
-
Ginkgetin derived from ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis mediated disruption of the nrf2 ho 1 axis in egfr wild type non small cell lung cancer
Phytomedicine, 2021Co-Authors: Jian Shu Lou, Karl Wah Keung Tsim, Liping Zhao, Zhi Hui Huang, Xia Yin Chen, William Chishing Tai, Yi Tao Chen, Tian XieAbstract:Abstract Background Cisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small-cell lung cancer (NSCLC). A recent study indicated that DDP could slightly induce non-apoptotic cell death ferroptosis, and the cytotoxicity was promoted by ferroptosis inducer. The agents enhancing the ferroptosis may therefore increase the anticancer effect of DDP. Several lines of evidence supporting the use of phytochemicals in NSCLC therapy. Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves, showed anticancer effects on NSCLC by triggering autophagy. Ferroptosis can be triggered by autophagy, which regulates redox homeostasis. Thus, we aimed to elucidate the possible role of ferroptosis involved in the synergistic effect of Ginkgetin and DDP in cancer therapy. Methods The promotion of DDP-induced anticancer effects by Ginkgetin was examined via a cytotoxicity assay and western blot. Ferroptosis triggered by Ginkgetin in DDP-treated NSCLC was observed via a lipid peroxidation assay, a labile iron pool assay, western blot, and qPCR. With ferroptosis blocking, the contribution of ferroptosis to Ginkgetin + DDP-induced cytotoxicity, the Nrf2/HO-1 axis, and apoptosis were determined via a luciferase assay, immunostaining, chromatin immunoprecipitation (CHIP), and flow cytometry. The role of ferroptosis in Ginkgetin + DDP-treated NSCLC cells was illustrated by the application of ferroptosis inhibitors, which was further demonstrated in a xenograft nude mouse model. Results Ginkgetin synergized with DDP to increase cytotoxicity in NSCLC cells, which was concomitant with increased labile iron pool and lipid peroxidation. Both these processes were key characteristics of ferroptosis. The induction of ferroptosis mediated by Ginkgetin was further confirmed by the decreased expression of SLC7A11 and GPX4, and a decreased GSH/GSSG ratio. Simultaneously, Ginkgetin disrupted redox hemostasis in DDP-treated cells, as demonstrated by the enhanced ROS formation and inactivation of the Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured NSCLC cells. Furthermore, blocking ferroptosis reversed the Ginkgetin-induced inactivation of Nrf2/HO-1 as well as the elevation of ROS formation, MMP loss, and apoptosis in DDP-treated NSCLC cells. Conclusion This study is the first to report that Ginkgetin derived from Ginkgo biloba leaves promotes DDP-induced anticancer effects, which can be due to the induction of ferroptosis.
-
Ginkgetin induces autophagic cell death through p62 sqstm1 mediated autolysosome formation and redox setting in non small cell lung cancer
Oncotarget, 2017Co-Authors: Jian Shu Lou, Gallant K L Chan, Huaiyou Wang, Jin Yan, Chauwing Wong, Zhongyu Zhou, Ping Yao, Tina T X Dong, Karl Wah Keung TsimAbstract:// Jian-Shu Lou 1, 2 , Wen-Chuan Bi 1, 2 , Gallant K.L. Chan 1, 2 , Yan Jin 1, 2 , Chau-Wing Wong 2 , Zhong-Yu Zhou 2 , Huai-You Wang 1, 2 , Ping Yao 2 , Tina T.X. Dong 1, 2 and Karl W.K. Tsim 1, 2 1 Shenzhen Research Institute, The Hong Kong University of Science and Technology, Shenzhen, China 2 Division of Life Science, Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China Correspondence to: Karl W.K. Tsim, email: botsim@ust.hk Keywords: autophagy, natural compounds, non-small cell lung cancer, p62, mTORC1 Received: July 12, 2017 Accepted: August 27, 2017 Published: October 16, 2017 ABSTRACT Promoting cell death by autophagy could be a novel treatment for cancer. The major player in autophagy, p62, serves as a good therapeutic target. Ginkgetin, a biflavonoid from Ginkgo biloba leaves, exhibited promising anticancer activity in non-small cell lung cancer cell lines, with an IC50 lower than that of cisplatin. This anticancer effect of Ginkgetin was illustrated in a xenograft nude mouse model. Ginkgetin induced autophagic cell death in A549 cells, and this effect was markedly reversed by chemical and genetic approaches. Ginkgetin showed potential binding affinity to p62. Upregulation of p62 through chemical and genetic means decreased cell death, lysosome acidification, and autophagosome formation, which consequently disrupted autolysosome formation. In addition, the decreased autophagy induced by p62 overexpression increased Nrf2/ARE activity and the oxygen consumption rate and decreased on formation of reactive oxygen species. These phenomena were exhibited in a reciprocal manner when p62 was knocked down. Thus, p62 may be a potential target in Ginkgetin-induced autophagic cell death, and Ginkgetin could be developed as a novel anticancer drug.