Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy

Feng, Tingting; Cao, Wei; Shen, Wanxiang; Zhang, Liang; Gu, Xinsheng; Guo, Yang; Tsai, Hsiang‐i; Li, Xuewen; Li, Jian; Zhang, Jingxuan; Li, Shan; Wu, Fuyun; Liu, Ying

doi:10.18632/oncotarget.13393

Cited by 70 publications

(50 citation statements)

References 46 publications

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“…Atn was identified to inhibit STAT3 binding to genomic DNA by disrupting hydrogen bond binding between DNA and STAT3. In addition, Atn augmented Taxotere ® -induced TNBC cell cytotoxicity (18). Here, we further showed that Atn was also able to cause a significant dose-and time-dependent decrease of CIP2A at both mRNA and protein levels in TNBCs (Fig.…”

Section: Discussionsupporting

confidence: 70%

“…Atn can also enhance the chemosensitivity of several cancer cells (Hepg2, HeLa, and K562), to cisplatin by inhibiting the STAT3 signaling pathway at high doses (17). As we showed in our previous study (18), Atn inhibited cell growth and induced apoptosis in TNBCs by inhibiting STAT3. We used computational docking and molecular dynamics simulation showed that Atn had high-affinity interaction with the SH2 domain of STAT3 with residues (Arg688, Pro689, and Pro695).…”

Section: Introductionmentioning

confidence: 54%

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Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A

et al. 2017

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Abstract.We have shown that a novel STAT3 inhibitor arctigenin (Atn) induces significant cytotoxicity in triple-negative breast cancer (TNBC) cells. This study further delineated molecular mechanisms where by Atn triggered cytotoxicity in TNBC cells. We found Atn can also inhibit metastasis in TNBC cells through cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. CIP2A is an endogenous inhibitor of protein phosphatase 2A (PP2A), which can increase the migration and invasion of various cancer cells. PP2A is a tumor suppressor, which is functionally defective in various cancers. Atn-induced metastasis inhibition was associated with reactivation of PP2A, downregulation of CIP2A and Akt phosphorylation. Silencing CIP2A enhanced Atn-induced metastasis inhibition and apoptosis in TNBCs. Furthermore, ectopic expression of CIP2A or inhibition of PP2A in TNBC cells abolished the effects of Atn. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A, at least in part, promotes the anti-metastasis effect induced by Atn. Our findings disclose the novel therapeutic mechanism of this targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 54%

Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A

et al. 2017

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“…As mentioned above, several studies have showed that apoptosis induction is a key mechanism of arctigenin to exert anticancer activities (Feng et al, ; Hsieh et al, ; Wang, Solorzano, et al, ). In the present study, we compared apoptosis induction by the 3′‐DMAG with that of arctigenin and found that 3′‐DMAG induced a quadrupling higher apoptosis than that by arctigenin.…”

Section: Discussionmentioning

confidence: 99%

“…Arctigenin exhibits distinct biological activities, including antiviral (Dias et al, ; Hayashi, Narutaki, Nagaoka, Hayashi, & Uesato, ), neuroprotection (Song et al, ; Zhu et al, ), antidiabetic (Huang et al, ; Zeng et al, ), and anticancer (Chen et al, ; Huang et al, ; Hsieh et al, ; Jeong, Hong, Jeong, & Koo, ; Lei, Gan, Zhao, Yu, & Hu, ; Li, Liang, Tian, & Hu, ; Maimaitili et al, ; Wang, Solorzano, et al, ; Susanti et al, ). A growing body of literature documents that arctigenin can induce cell cycle arrests, apoptosis, autophagy, and antimetastasis in multiple types of cancer cells, including prostate (Wang, Solorzano, et al, ), breast (Feng et al, ; Hsieh et al, ; Lou, Zhu, Zhao, Zhu, & Zhao, ; Maxwell, Lee, Kim, & Nam, ), lung (Lei et al, ), liver (Susanti et al, ), gastric (Jeong et al, ), ovarian (Huang et al, ), colon cancer (Li et al, ), and glioma (Maimaitili et al, ). The anticancer efficacy of arctigenin in vivo also has been reported in human cancer cell xenograft model in athymic nude mice (Feng et al, ; Wang, Solorzano, et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…A growing body of literature documents that arctigenin can induce cell cycle arrests, apoptosis, autophagy, and antimetastasis in multiple types of cancer cells, including prostate (Wang, Solorzano, et al, ), breast (Feng et al, ; Hsieh et al, ; Lou, Zhu, Zhao, Zhu, & Zhao, ; Maxwell, Lee, Kim, & Nam, ), lung (Lei et al, ), liver (Susanti et al, ), gastric (Jeong et al, ), ovarian (Huang et al, ), colon cancer (Li et al, ), and glioma (Maimaitili et al, ). The anticancer efficacy of arctigenin in vivo also has been reported in human cancer cell xenograft model in athymic nude mice (Feng et al, ; Wang, Solorzano, et al, ).…”

Section: Introductionmentioning

confidence: 99%

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3′‐Desmethylarctigenin induces G2/M cell cycle arrest and apoptosis through reactive oxygen species generation in hepatocarcinoma cells

Zhang

Wang

Liu

et al. 2019

Phytotherapy Research

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Previous studies have shown that arctigenin is a promising chemopreventive or therapeutic agent against various cancers. However, less is known about anticancer activity of 3′‐desmethylarctigenin (3′‐DMAG), which is a biotransformed product from arctigenin or arctin. In this study, we compared the anticancer activity of 3′‐DMAG with its parent compound arctigenin and demonstrated that 3′‐DMAG exerted a more potent inhibitory effect on HepG2 cells than arctigenin. Mechanistically, reactive oxygen species generation played an apical role in 3′‐DMAG‐induced G2/M cell cycle arrest and apoptosis in HepG2 cells. Furthermore, the Chk2–Cdc25c–Cdc2–cyclin B1 cascade was found to contribute to the cell cycle arrest, whereas the activation of mitochondrial pathway was involved in the cell apoptosis by 3′‐DMAG. Additionally, a mouse xenograft hepatocellular carcinoma model was used to evaluate the antitumor effect of 3′‐DMAG in vivo, and the results indicated that 3′‐DMAG treatment significantly inhibited tumor growth without apparent toxicity. Taken together, 3′‐DMAG is highly effective against liver cancer both in vitro and in vivo. The findings of the present study suggest that this compound deserves to be further investigated for its potential anticancer activity.

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Polyphyllin I Inhibits Proliferation and Induces Apoptosis by Downregulating AML1‐ETO and Suppressing C‐KIT/Akt Signaling in t(8;21) Acute Myeloid Leukemia

Chai

et al. 2018

Chemistry & Biodiversity

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Polyphyllin I (PPI), a bioactive constituent extracted from traditional medicinal herbs, is cytotoxic to several cancer types. However, whether PPI can be used to treat t(8;21) acute myeloid leukemia (AML) cells requires further investigation. Here, we determined the inhibitory effects of PPI on t(8;21) AML cells by Cell Counting Kit-8 (CCK-8) and the trypan blue dye exclusion assay. DAPI staining and Wright-Giemsa staining were performed to check for apoptosis. Detection of apoptotic protein and AML1-ETO signaling protein expression were conducted by Western blot analysis. Our results suggested that PPI decreased growth and induced apoptosis in a dosage-dependent manner in the t(8;21) AML cell line Kasumi-1. PPI significantly downregulated AML1-ETO expression in a dosage- and time-dependent manner. PPI also upregulated P21 and downregulated survivin expression by reducing AML1-ETO. Mechanistically, PPI significantly reduced the expression of C-KIT, another therapeutic target for AML with t(8;21), followed by inhibition of Akt signaling. These results suggest that PPI can suppress growth and induce apoptosis of t(8;21) AML by suppressing the AML1-ETO and C-KIT/Akt signaling pathways. Therefore, PPI may be an anticancer therapeutic to treat t(8;21) AML.

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Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy

Cited by 70 publications

References 46 publications

Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A

Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A

3′‐Desmethylarctigenin induces G2/M cell cycle arrest and apoptosis through reactive oxygen species generation in hepatocarcinoma cells

Polyphyllin I Inhibits Proliferation and Induces Apoptosis by Downregulating AML1‐ETO and Suppressing C‐KIT/Akt Signaling in t(8;21) Acute Myeloid Leukemia

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