The effects of bufadienolides on HER2 overexpressing breast cancer cells

Wang, Tianjiao; Mu, Lin; Jin, Haifeng; Zhang, Peng; Wang, Yueyue; Ma, Xiaochi; Pan, Jinjin; Miao, Jian; Yuan, Yuhui

doi:10.1007/s13277-015-4381-3

Cited by 10 publications

(7 citation statements)

References 49 publications

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“…For instance, our previous study showed that ARE and BFU can inhibit SRC‐1 and SRC‐3 expression in HER2‐positive breast cancer cells. Additionally, ARE and BFU can block breast cancer, glioma, and lung cancer cell proliferation 39,72‐74 . In our study, ARE and BFU suppressed the expression of SRC‐1 in GBM cells.…”

Section: Discussionsupporting

confidence: 55%

“…Our previous study reported that arenobufagin (ARE) and bufalin (BFU; SRC inhibitor), homogeneous bufadienolides, could inhibit SRC-1 expression in HER2-overexpressing breast cancer cells. 39 Thus, in this study, ARE and BFU were used to treat LN229-EV, LN229-SRC1, and U251 cells at 50 nmol/L for 48 hours. The results showed that the expression of SRC-1, XIST, and KLF4 had all obviously declined in control and SRC-1 overexpression cells (Figure 8A-C).…”

Section: Arenobufagin and Bufalin Inhibit Proliferation And Stemness ...mentioning

confidence: 99%

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Steroid receptor coactivator‐1 enhances the stemness of glioblastoma by activating long noncoding RNA XIST/miR‐152/KLF4 pathway

Gong

Wang

et al. 2020

Cancer Science

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Glioblastoma (GBM) recurrence is attributed to the presence of therapy‐resistant glioblastoma stem cells. Steroid receptor coactivator‐1 (SRC‐1) acts as an oncogenic regulator in many human tumors. The relationship between SRC‐1 and GBM has not yet been studied. Herein, we investigate the role of SRC‐1 in GBM. In this study, we found that SRC‐1 expression is positively correlated with grades of glioma and inversely correlated with glioma patient’s prognosis. Steroid receptor coactivator‐1 promotes the proliferation, migration, and tumor growth of GBM cells. Notably, SRC‐1 knockdown suppresses the stemness of GBM cells. Mechanistically, long noncoding RNA X‐inactive specific transcript (XIST) is regulated by SRC‐1 at the posttranscriptional level and mediates the function of SRC‐1 in promoting stemness‐like properties of GBM. Steroid receptor coactivator‐1 can promote the expression of Kruppel‐like factor 4 (KLF4) through the XIST/microRNA (miR)‐152 axis. Additionally, arenobufagin and bufalin, SRC small molecule inhibitors, can reduce the proliferation and stemness of GBM cells. This study reveals SRC‐1 promotes the stemness of GBM by activating the long noncoding RNA XIST/miR‐152/KLF4 pathway and provides novel markers for diagnosis and therapy of GBM.

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Section: Discussionsupporting

confidence: 55%

Section: Arenobufagin and Bufalin Inhibit Proliferation And Stemness ...mentioning

confidence: 99%

Steroid receptor coactivator‐1 enhances the stemness of glioblastoma by activating long noncoding RNA XIST/miR‐152/KLF4 pathway

Gong

Wang

et al. 2020

Cancer Science

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“…As an inhibitor of SRC-3, bufalin reduced tumor growth in an MDA-MB-231-LM3.3 xenograft tumor model. Yuan et al [42] have found that ABF inhibits the proliferation and survival of HER2-overexpressing breast cancer MCF-7/HER2 and T47D/HER2 cells through the inhibition of AKT, ERK and E2F1. Instead of these reported mechanisms, we find that ABF-induced phosphorylation of YAP through JNK signaling enhances the p73-mediated transcription of Bax and p53AIP1 , and subsequently induces apoptosis in MCF-7 cells.…”

Section: Discussionmentioning

confidence: 99%

Arenobufagin induces MCF-7 cell apoptosis by promoting JNK-mediated multisite phosphorylation of Yes-associated protein

Deng

Peng

et al. 2018

Cancer Cell Int

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BackgroundIt has been demonstrated that bufadienolides exert potent anti-cancer activity in various tumor types. However, the mechanisms that underlie their anti-cancer properties remain unclear. Yes-associated protein, a key effector of Hippo signaling, functions as a transcription coactivator, plays oncogenic and tumor suppressor roles under different conditions. Here, we report that arenobufagin (ABF), a representative bufadienolide, induced breast cancer MCF-7 cells to undergo apoptosis, which occurred through the JNK-mediated multisite phosphorylation of YAP.MethodsCytotoxicity was examined using an MTT assay. ABF-induced apoptosis was measured with a TUNEL assay and Annexin V-FITC/PI double staining assay. Western blotting, immunofluorescence, qRT-PCR and coimmunoprecipitation were employed to assess the expression levels of the indicated molecules. Lose-of-function experiments were carried out with siRNA transfection and pharmacological inhibitors. ABF-induced phosphopeptides were enriched with Ti4+-IMAC chromatography and further subjected to reverse-phase nano-LC–MS/MS analysis.ResultsABF significantly reduced the viability of MCF-7 cells and increased the percentage of early and late apoptotic cells in a concentration- and time-dependent manner. Following ABF treatment, YAP accumulated in the nucleus and bound to p73, which enhanced the transcription of the pro-apoptotic genes Bax and p53AIP1. YAP knock-down significantly attenuated ABF-induced apoptotic cell death. Importantly, we found that the mobility shift of YAP was derived from its phosphorylation at multiple sites, including Tyr357. Moreover, mass spectrometry analysis identified 19 potential phosphorylation sites in YAP, with a distribution of 14 phosphoserine and 5 phosphothreonine residues. Furthermore, we found that the JNK inhibitor SP600125 completely diminished the mobility shift of YAP and its phosphorylation at Tyr357, the binding of YAP and p73, the transcription of Bax and p53AIP1 as well as the apoptosis induced by ABF. These data indicate that ABF induced YAP multisite phosphorylation, which was associated with p73 binding, and that apoptosis was mediated by the JNK signaling pathway.ConclusionsOur data demonstrate that ABF suppresses MCF-7 breast cancer proliferation by triggering the pro-apoptotic activity of YAP, which is mediated by JNK signaling-induced YAP multisite phosphorylation as well as its association with p73. The present work not only provides additional information on the use of ABF as an anti-breast cancer drug, but also offers evidence that the induction of the tumor suppressor role of YAP may be a therapeutic strategy.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0706-9) contains supplementary material, which is available to authorized users.

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“…Studies showed that ABG and BF could significantly inhibit the proliferation and survival of HER2 overexpressing breast cancer cells, and downregulate the expression of SRC-1, SRC-3, nuclear transcription factor E2F1, phosphorylated AKT and ERK. The combination of low-dose bufadienolides and tamoxifen could significantly enhance the inhibitory effect of tamoxifen on HER2 overexpression breast cancer cells, which suggested that ABG and BF might be potential adjuvant therapy drugs for the treatment of HER2 overexpression breast cancer [ 30 ]. Paclitaxel (PTX) is an effective drug for the treatment of cancer [ 31 ].…”

Section: Pharmacological Activities Of Bufadienolidesmentioning

confidence: 99%

Novel Strategies for Solubility and Bioavailability Enhancement of Bufadienolides

Shao

et al. 2021

Molecules

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Toad venom contains a large number of bufadienolides, which have a variety of pharmacological activities, including antitumor, cardiovascular, anti-inflammatory, analgesic and immunomodulatory effects.. The strong antitumor effect of bufadienolides has attracted considerable attention in recent years, but the clinical application of bufadienolides is limited due to their low solubility and poor bioavailability. In order to overcome these shortcomings, many strategies have been explored, such as structural modification, solid dispersion, cyclodextrin inclusion, microemulsion and nanodrug delivery systems, etc. In this review, we have tried to summarize the pharmacological activities and structure–activity relationship of bufadienolides. Furthermore, the strategies for solubility and bioavailability enhancement of bufadienolides also are discussed. This review can provide a basis for further study on bufadienolides.

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The effects of bufadienolides on HER2 overexpressing breast cancer cells

Cited by 10 publications

References 49 publications

Steroid receptor coactivator‐1 enhances the stemness of glioblastoma by activating long noncoding RNA XIST/miR‐152/KLF4 pathway

Steroid receptor coactivator‐1 enhances the stemness of glioblastoma by activating long noncoding RNA XIST/miR‐152/KLF4 pathway

Arenobufagin induces MCF-7 cell apoptosis by promoting JNK-mediated multisite phosphorylation of Yes-associated protein

Novel Strategies for Solubility and Bioavailability Enhancement of Bufadienolides

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