Fluvastatin Prevents Lung Adenocarcinoma Bone Metastasis by Triggering Autophagy

Yang, Zuozhang; Su, Zhenyi; DeWitt, Judy Park; Xie, Lin; Chen, Yongbin; Li, Xiaojuan; Han, Lei; Li, Dongqi; Xia, Junfeng; Zhang, Ya; Yang, Yihao; Jin, Congguo; Zhang, Jing; Su, Li; Li, Kun; Zhang, Zhiping; Qu, Xin; He, Zewei; Chen, Yanjin; Shen, Yan; Ren, Mingyan; Yuan, Zhongqin

doi:10.1016/j.ebiom.2017.04.017

Cited by 68 publications

(56 citation statements)

References 43 publications

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“…Similar results were observed in airway mesenchymal cells using ATG7 shRNA [41]. Fluvastatin mediated attenuation of lung adenocarcinoma bone metastasis via induction of autophagy in lung adenocarcinoma cells was prevented after deletion of the ATG5 or ATG7 gene in SPC-A-1 cells [37].…”

supporting

confidence: 80%

“…Conversely, atorvastatin drives the autophagy pathway in human bladder cancer cells [80]. Similar results were observed in lung adenocarcinoma cells, A549 and SPC-A-1, after treatment with 10 lM of fluvastatin for 24-36 h [37]. These inconsistencies with our findings may be due to differences in Simva doses used or cell confluence at the time of treatment [48].…”

supporting

confidence: 65%

“…MEV cascade independent mechanisms are involved in the induction of apoptosis in cells treated with statins . Importantly, the modulation of autophagy was shown to be involved in statin‐induced cell death .…”

Section: Introductionmentioning

confidence: 99%

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Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

et al. 2019

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Temozolomide (TMZ) is a chemotherapy agent used to treat Grade IV astrocytoma, also known as glioblastoma (GBM). TMZ treatment causes DNA damage that results in tumor cell apoptosis and increases the survival rate of GBM patients. However, chemoresistance as a result of TMZ‐induced autophagy significantly reduces this anticancer effects over time. Statins are competitive inhibitors of HMG‐CoA reductase, the rate‐limiting enzyme of the mevalonate (MEV) cascade. Statins are best known for their cholesterol (CH)‐lowering effect. Long‐term consumption of statins, prior to and in parallel with other cancer therapeutic approaches, has been reported to increase the survival rate of patients with various forms of cancers. In this study, we investigated the potentiation of TMZ‐induced apoptosis by simvastatin (Simva) in human GBM cell lines and patient GBM cells, using cell monolayers and three‐dimensional cell culture systems. The incubation of cells with a combination of Simva and TMZ resulted in a significant increase in apoptotic cells compared to cells treated with TMZ alone. Incubation of cells with CH or MEV cascade intermediates failed to compensate the decrease in cell viability induced by the combined Simva and TMZ treatment. Simva treatment inhibited the autophagy flux induced by TMZ by blocking autophago‐lysosome formation. Our results suggest that Simva sensitizes GBM cells to TMZ‐induced cell death in a MEV cascade‐independent manner and identifies the inhibition of autophagosome‐lysosome fusion as a promising therapeutic strategy in the treatment of GBM.

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supporting

confidence: 80%

supporting

confidence: 65%

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Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

et al. 2019

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“…32 Numerous studies suggest that autophagy plays a pivotal role in modulating tumor cell motility and invasion, cancer stem cell viability and differentiation, resistance to anoikis, EMT, tumor cell dormancy, escape from immune surveillance, and metastasis. 35 Zhang et al demonstrated that tetrandrine inhibited HCC metastasis through modulating the autophagy-dependent Wnt/β-catenin and MTA1 signaling, and autophagic cell death acted as a barrier against metastasis. In FIGURE 7 Illustration of present work gastric cancer cells and corresponding tumor xenografts in mice, Qin et al found that inhibiting autophagy could enhance EMT and metastasis via ROS generation.…”

Section: Discussionmentioning

confidence: 99%

“…In 34 Similarly, fluvastatin inhibited bone metastasis of lung adenocarcinoma by inducing autophagy. 35 Zhang et al demonstrated that tetrandrine inhibited HCC metastasis through modulating the autophagy-dependent Wnt/β-catenin and MTA1 signaling, and autophagic cell death acted as a barrier against metastasis. 36 Consistent with these studies, our findings indicated that XAG suppressed HCC cell metastasis by inducing autophagic cell death.…”

Section: Discussionmentioning

confidence: 99%

Autophagy induction by xanthoangelol exhibits anti‐metastatic activities in hepatocellular carcinoma

Yang

Xie

Liu

et al. 2019

Cell Biochemistry & Function

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Xanthoangelol (XAG), a prenylated chalcone isolated from the Japanese herb Angelica keiskei Koidzumi, has been reported to exhibit antineoplastic properties. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC), and the relevant mechanisms are not known. Herein, we evaluated the effect of XAG against HCC in vitro and in vivo. Although XAG treatment did not significantly reduce the viability of the Hep3B and Huh7 cell lines, it suppressed cell migration, invasion, and EMT. This anti-metastatic effect of XAG was due to induction of autophagy, because treatment with the autophagy inhibitor 3-methyadenine (3-MA) or knockdown of the pro-autophagy Beclin-1 effectively abrogated the XAG-induced suppression of metastasis. Mechanistically, XAG induced autophagy via activation of the AMPK/mTOR signaling pathway, and XAG treatment dramatically increased the expression of p-AMPK while decreasing p-mTOR expression. In addition, blocking AMPK/mTOR axis with compound C abrogated the autophagy-mediated inhibition of metastasis. The murine model of HCC metastasis also showed that XAG effectively reduced the number of metastatic pulmonary nodules. Taken together, our results revealed that autophagy via the activation of AMPK/mTOR pathway is essential for the anti-metastatic effect of XAG against HCC. These findings not only contribute to our understanding of the anti-tumor activity of XAG but also provide a basis for its clinical application in HCC. Before this study, evidence of XAG on HCC was purely anecdotal; present study provides the first comprehensive assessments of XAG on HCC metastasis and investigates its underlying mechanism. Results suggest that XAG exerts anti-metastatic properties against HCC through inducing autophagy which is mediated by the activation of AMPK/mTOR signaling pathway. This research extends our knowledge about the antineoplastic properties of XAG and suggests that induction autophagy may represent future treatment strategies for metastatic HCC. KEYWORDSAMPK/mTOR, autophagy, HCC, metastasis, xanthoangelol Xiuwei Yang and Jing Xie are co-first authors and contributed equally to this work.

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Preclinical activity of fluvastatin‐loaded self‐nanoemulsifying delivery system against breast cancer models: Emphasis on apoptosis

Elimam

Hussein

Abdel-Latif

et al. 2022

J of Cellular Biochemistry

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Statins trigger apoptotic cell death in some types of growing tumor cells in a cholesterol-lowering-independent manner. Self-nanoemulsifying delivery systems (SNEDs) are potentially effective for the suppression of breast cancer development. This study aims to investigate the potential anticancer activity of fluvastatin (FLV)-SNEDs in breast cancer while comparing it with FLV in vitro as well as in vivo exploiting/using MDA-MB-231 and Erhlich ascites carcinoma (EAC)-bearing mice, respectively. Biochemical analysis of liver and kidney functions, oxidative stress markers, and histopathological examinations of such tumor tissues were performed showing the potentiality of SNEDs as a nanocarrier for antitumor agents. FLV-SNEDs demonstrated more potent anticancer activity compared to FLV on MDA-MB-231 and hepatocellular carcinoma (HepG2) cells. In vivo experiments on the EACbearing mice model indicated that FLV and-to a greater extent-FLV-SNEDs ameliorated EAC-induced hepatotoxicity and nephrotoxicity. FLV or FLV-SNEDs evidently reduced the percent of Ki-67 +ve EAC cells by 57.5% and 86.5% in comparison to the vehicle-treated EAC group. In addition, FLV or FLV-SNEDs decreased Bcl-2 levels in serum and liver specimens. In contrast, FLV or FLV-SNEDs significantly activated the executioner caspase-3.Simultaneously, both FLV and FLV-SNEDs stimulated p53 signaling and modulated Bcl-2 protein levels in treated cells. Collectively, these results support the contribution of apoptotic cell death in mediating the anticancer activities of FLV and FLV-SNEDs against murine EAC model in vivo. This study provides new understandings of how FLV and FLV-SNEDs regulate EAC cell viability via upregulation of p53 signaling, and through modulation of cleaved caspase-3 as well as antiapoptotic Bcl-2 marker.

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Fluvastatin Prevents Lung Adenocarcinoma Bone Metastasis by Triggering Autophagy

Cited by 68 publications

References 43 publications

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

Simvastatin increases temozolomide‐induced cell death by targeting the fusion of autophagosomes and lysosomes

Autophagy induction by xanthoangelol exhibits anti‐metastatic activities in hepatocellular carcinoma

Preclinical activity of fluvastatin‐loaded self‐nanoemulsifying delivery system against breast cancer models: Emphasis on apoptosis

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