Ginkgetin induces autophagic cell death through p62/SQSTM1-mediated autolysosome formation and redox setting in non-small cell lung cancer

Lou, Jian-Shu; Bi, Wenchuan; Chan, Gallant Kar-Lun; Jin, Yan; Wong, Chau-Wing; Zhou, Zhong‐Yu; Wang, Huaiyou; Yao, Ping; Dong, Tina Ting Xia; Tsim, Karl Wah Keung

doi:10.18632/oncotarget.21862

Cited by 45 publications

(30 citation statements)

References 67 publications

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“…Different studies on ginkgetin have proposed a series of pharmacological activities [28]. Ginkgetin exerts inhibitory effects on different types of cancers including prostate cancer [29], breast cancer [30], non-small cell lung cancer [31], and colon cancer [32]. Moreover, ginkgetin has been shown to exhibit cytotoxic effects in ovarian and prostate cancers [29,33].…”

Section: Discussionmentioning

confidence: 99%

Synergy of Ginkgetin and Resveratrol in Suppressing VEGF-Induced Angiogenesis: A Therapy in Treating Colorectal Cancer

Chan

Duan

et al. 2019

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

Synergy of Ginkgetin and Resveratrol in Suppressing VEGF-Induced Angiogenesis: A Therapy in Treating Colorectal Cancer

Chan

Duan

et al. 2019

Cancers

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“…Recent studies on various substances have reported that autophagy plays a paradoxical role in anti-tumor therapy. Induction of autophagic cell death by small molecules contributes to the enhancement of anti-tumor activity of chemotherapy or radiation therapy, whereas autophagy-dependent anti-apoptotic responses induced by chemotherapy have negative impacts on anti-tumor treatment through inhibition of the mTOR pathway 17,18 . To our best knowledge, no association between anti-tumor effects of PAM and autophagy has been reported.…”

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confidence: 99%

Plasma-activated medium promotes autophagic cell death along with alteration of the mTOR pathway

Yoshikawa

Liu

Nakamura

et al. 2020

Sci Rep

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the biological function of non-thermal atmospheric pressure plasma has been widely accepted in several types of cancer. We previously developed plasma-activated medium (pAM) for clinical use, and demonstrated that PAM exhibits a metastasis-inhibitory effect on ovarian cancer through reduced MMP-9 secretion. However, the anti-tumor effects of PAM on endometrial cancer remain unknown. In this study, we investigated the inhibitory effect of PAM on endometrial cancer cell viability in vitro.Our results demonstrated that AMEC and HEC50 cell viabilities were reduced by PAM at a certain PAM ratio, and PAM treatment effectively increased autophagic cell death in a concentration dependent manner. in addition, we evaluated the molecular mechanism of pAM activity and found that the mtoR pathway was inactivated by pAM. Moreover, our results demonstrated that the autophagy inhibitor MHY1485 partially inhibited the autophagic cell death induced by PAM treatment. These findings indicate that pAM decreases the viability of endometrial cancer cells along with alteration of the mtoR pathway, which is critical for cancer cell viability. collectively, our data suggest that pAM inhibits cell viability while inducing autophagic cell death in endometrial cancer cells, representing a potential novel treatment for endometrial cancer.Endometrial cancer is the most common gynecologic malignancy in Japan, with an estimated 13,600 new cases diagnosed in 2015 1 . The incidence of new cases is believed to have increased over the last few decades due to increased levels of obesity, hypertension, and diabetes mellitus, particularly in South Africa and several Asian countries including Japan 1,2 . Although the majority of endometrial cancer patients are diagnosed in the early stage and outcomes are generally favorable because of the typical symptom of irregular vaginal bleeding in women of menopausal age, the prognoses of patients in advanced stages not amenable to localized therapies remain poor 1 . Indeed, a frequent pattern of progression and recurrence is peritoneal metastasis, which is often resistant to systemic chemotherapy 3 . In addition, cytotoxic agents for endometrial cancer are relatively limited compared with other gynecologic malignancies. Thus, there is an increasing demand for novel approaches to peritoneal dissemination.For the past decade, nonequilibrium atmospheric pressure plasma (NEAPP) has been studied for its clinical applications such as sterilization, wound healing, and cancer therapy 4-6 . NEAPP represents a partially ionized gas with energy mainly accumulated as free electrons 7 . Recent studies have revealed that in addition to the direct irradiation of NEAPP to bacteria or tissues, indirect plasma treatment with plasma-activated medium (PAM) and plasma-activated lactate (PAL), which are activated by NEAPP, exhibit anti-tumor activity in several types of cancer, including ovarian, pancreatic, colorectal and gastric cancers 4,8-13 . The molecular mechanism of the anti-tumor effects triggered by PAM have been investigat...

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“…Ginkgetin, a bi avonoid from Ginkgo biloba leaves, exhibited cytotoxicity in cultured A549 cells 15 . Here, ginkgetin was combined with DDP at various concentrations in applying onto cultured A549 cells.…”

Section: Ginkgetin Promotes Ddp-induced Cytotoxicitymentioning

confidence: 99%

“…The concentration of total glutathione, or GSSG, was calculated via standard curve, and GSH level was calculated as: GSH = (total glutathione-GSSG) × 2. The ratio of GSH/GSSG was calculated as [GSH]/[GSSG].Xenograft nude mice modelThe establishment of xenograft nude mouse model and ginkgetin preparation were conducted as previously described15 . Brie y, when tumours on transplanted nude mice reached around 100 mm 3 , the mice were randomized divided into eight groups: control, ginkgetin, DDP, ginkgetin + DDP, UAMC 3203, ginkgetin + UAMC 3203, DDP + UAMC 3203, ginkgetin + DDP + UAMC 3203.…”

mentioning

confidence: 99%

Ferroptosis induction induced by ginkgetin enhances therapeutic effect of cisplatin in EGFR wild type non-small cell lung cancer

Lou¹,

Zhao²,

Huang³

et al. 2020

Preprint

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Background Cisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small cell lung cancer (NSCLC). Recent study indicates that DDP could slightly induce non apoptotic cell death ferroptosis, and the cytotoxicity was promoted by ferroptosis inducer. The agents enhancing ferroptosis level therefore may increase anticancer effect of DDP. Several lines of evidence support the usage of phytochemicals in therapy of NSCLC. Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves, showed anti-cancer effect on NSCLC both in vitro and in vivo, which could strongly trigger autophagy. Ferroptosis can be triggered by autophagy, and which regulates redox homeostasis. Thus, we aim to elucidate the possible role of ferroptosis induction in accounting for synergy of ginkgetin with DDP in cancer therapy.Methods Ginkgetin promoted DDP-induced anticancer effect was observed via cytotoxicity assay and western blot. Ferroptosis triggered by ginkgetin in DDP treated NSCLC was observed via lipid peroxidation assay, labile iron pool assay, western blot, and QPCR. With ferroptosis blocking, the contribution of ferroptosis on ginkgetin + DDP induced cytotoxicity, Nrf2/HO-1 axis and apoptosis were determined via 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 inhibitor, which was further demonstrated in xenograft nude mice model.Results Ginkgetin synergized cisplatin in cytotoxicity in NSCLC cells, which concomitant with increased labile iron pool and lipid peroxidation: both these processes were the key characteristics of ferroptosis. The induction of ferroptosis, mediated by ginkgetin, was further confirmed by decline expressions of SLC7A11, GPX4 and GSH/GSSG ratio. In parallel, ginkgetin disrupted redox hemeostasis in DDP-treated cells, demonstrated by the enhanced ROS formation and inactivation on 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 gingketin-induced inactivation on Nrf2/HO-1, as well as the elevation on ROS formation, MMP loss and apoptosis in DDP-treated NSCLC cells.Conclusion This study firstly reported that ginkgetin promoted DDP-induced anticancer effect, which could be accounted by induction of ferroptosis.

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Ginkgetin induces autophagic cell death through p62/SQSTM1-mediated autolysosome formation and redox setting in non-small cell lung cancer

Cited by 45 publications

References 67 publications

Synergy of Ginkgetin and Resveratrol in Suppressing VEGF-Induced Angiogenesis: A Therapy in Treating Colorectal Cancer

Synergy of Ginkgetin and Resveratrol in Suppressing VEGF-Induced Angiogenesis: A Therapy in Treating Colorectal Cancer

Plasma-activated medium promotes autophagic cell death along with alteration of the mTOR pathway

Ferroptosis induction induced by ginkgetin enhances therapeutic effect of cisplatin in EGFR wild type non-small cell lung cancer

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