Natural Sesquiterpene Lactones Enhance Chemosensitivity of Tumor Cells through Redox Regulation of STAT3 Signaling

Butturini, Elena; Prati, Alessandra Carcereri de; Boriero, Diana; Mariotto, Sofia

doi:10.1155/2019/4568964

Cited by 17 publications

(18 citation statements)

References 153 publications

(124 reference statements)

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“…14,15 Several natural sesquiterpene lactones, such as alantolactone, parthenolide, and dehydrocostuslactone, exhibit anti-TNBC effects via downregulation of p-STAT3 expression. 25 In our study, we found that BA inhibited the expression of STAT3 in MDA-MB-231 and MDA-MB-468 cells, indicating another potential route for the anti-TNBC activity of BA.…”

Section: Ba Inhibited Cancer Cell Proliferation In Vivosupporting

confidence: 52%

Brevilin A, a Natural Sesquiterpene Lactone Inhibited the Growth of Triple-Negative Breast Cancer Cells via Akt/mTOR and STAT3 Signaling Pathways

Zhao

Lin

Mok

et al. 2020

OTT

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Purpose: Triple-negative breast cancer (TNBC) is a a breast cancer subtype characterized by a lack of estrogen receptor, progesterone receptor and human epidermal growth receptor 2 and is associated with poorer prognoses when compared to other breast cancers. Thus, novel anti-cancer agents with high efficacy are urgently needed. Brevilin A (BA), a natural sesquiterpene lactone, has been reported to exhibit anti-cancer effects. However, the effects of BA on TNBC have not yet been demonstrated. In this study, we investigated the anti-TNBC effects and the underlying mechanism of BA, in vitro and in vivo. Methods: Two TNBC cell lines and a xenograft mouse model were employed to assess the effects of BA. Cell viability was detected by MTT assay. Cell cycle status and apoptosis were evaluated by flow cytometry. Cell migration was measured by wound-healing assay. Protein expression was measured by Western blotting analysis. The in vivo anti-cancer activity of BA was assessed in orthotopic tumor xenograft mice. Results: BA significantly inhibited the growth of TNBC cells in a dose-and time-dependent manner via induction of cell cycle arrest at G2/M phase arrest and apoptosis. BA also inhibited tumor cell migration. BA significantly downregulated the expression of Akt, mTOR, Stat3 and their phosphorylation, and thus inhibiting the activation of the Akt/mTOR and STAT3 signaling pathways. Furthermore, oral administration of BA at 25 or 50 mg/kg leads to significant inhibition of tumor growth and proliferation in tumor xenograft model mice. Conclusion: BA significantly inhibited the growth and migration of TNBC cells, and induced cell cycle arrest and apoptosis. These inhibitory effects were associated with the suppression of the Akt/mTOR and Stat3 signal pathways. Based on our findings, BA possesses a promising candidate for development as an anti-cancer therapeutic drug against TNBC.

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Section: Ba Inhibited Cancer Cell Proliferation In Vivosupporting

confidence: 52%

Brevilin A, a Natural Sesquiterpene Lactone Inhibited the Growth of Triple-Negative Breast Cancer Cells via Akt/mTOR and STAT3 Signaling Pathways

Zhao

Lin

Mok

et al. 2020

OTT

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“…GSH levels associate with chemosensitivity and programmed cell death of tumor cells. 12,13 However, the content and the effect of GSH in EOC have not been fully researched.…”

Section: Introductionmentioning

confidence: 99%

PSAT1 Regulated Oxidation-Reduction Balance Affects the Growth and Prognosis of Epithelial Ovarian Cancer

Zhang¹,

Li²,

Dong³

et al. 2020

OTT

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Introduction: A growing number of studies have found that the serine-glycine biosynthesis pathway is highly activated for biosynthesis in cancer progression and metastasis. Phosphoserine aminotransferase 1 (PSAT1) catalyzes the second step of the serine-glycine biosynthesis pathway; the effects and mechanism of PSAT1 in epithelial ovarian cancer (EOC) remains unclear. Materials and Methods: The expression of PSAT1 in clinical EOC samples and normal ovarian tissues was conducted by RT-PCR, Western blot, and immunohistochemical staining. Survival analysis of PSAT1 in ovarian cancer was performed by using the public database. Following the downregulation of PSAT1, the cell growth, cell apoptosis, and cell cycle in ovarian cancer cells were respectively examined by the soft agar colony formation assay and flow cytometry analysis. Then the glutathione (GSH) levels, the GSH/GSSG ratio, the NADPH/NADP ratio, and the cellular reactive oxygen species (ROS) levels were tested to analyze the oxidation-reduction balance in PSAT1-depleted ovarian cancer cells. Results: PSAT1 is markedly over-expressed in clinical EOC samples (n = 90) compared to that in normal ovarian tissues (n = 10), and the expression of PSAT1 is correlated with histological subtype, FIGO stage, histological grade, lymph node metastasis, distant metastasis and the presence of ascites. Public database analysis shows that higher PSAT1 indicates poor survival in EOC patients. Downregulation of PSAT1 in EOC cells inhibits growth, induces apoptosis and cell cycle arrest in vitro. EOC cells with high PSAT1 levels have increased a higher GSH (reduced glutathione)/GSSG (oxidized glutathione) ratio and lower reactive oxygen species (ROS) content. The cancer-killing effects of PSAT1 knockdown are reversed by exogenous glutathione. PSAT1 participates in cancer growth by regulating oxidation-reduction balance. Conclusion: Therefore, these results highlight the potential of PSAT1 inhibitors or metabolic substrate deprivation as therapeutic strategies for treating patients with EOC, especially those with advanced stages of cancer.

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“…Xanthium fruit extracts contain various natural compounds including xanthanolides (Chen et al, 2013; Jiang et al, 2017; Vasas & Hohmann, 2011; Wang et al, 2013). Among them, we were interested in xanthanolides because they are already known to suppress the proliferation of cancer cells through multiple mechanisms, including the suppression of telomerase activity, inhibition of STAT3 activation, and promotion of apoptosis (Butturini, Carcereri de Prati, Boriero, & Mariotto, 2019; Fang et al, 2018; Vasas & Hohmann, 2011). UPLC‐PDA‐QTof‐MS analyses were carried out on a Micromass QTof Premier™ instrument equipped with an ACQUITY BEHC 18 chromatography column.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the EA fraction of the Xanthium fruit extracts decreased the proliferation of the DU145 cancer cells in a time-and concentration-dependent manner(Figure 1b).These results implied that Xanthium fruit extracts contain STAT3 inhibitory compounds.3.2 | Isolation of the STAT3 inhibitory compound EXT from the Xanthium fruit extractsXanthium fruit extracts contain various natural compounds includingxanthanolides(Chen et al, 2013;Jiang et al, 2017;Vasas & Hohmann, 2011;Wang et al, 2013). Among them, we were interested in xanthanolides because they are already known to suppress the proliferation of cancer cells through multiple mechanisms, including the suppression of telomerase activity, inhibition of STAT3 activation, and promotion of apoptosis(Butturini, Carcereri de Prati, Boriero, & Mariotto, 2019;Fang et al, 2018;Vasas & Hohmann, 2011). UPLC-PDA-QTof-MS analyses were carried out on a Micromass QTof Pre-mier™ instrument equipped with an ACQUITY BEHC 18 chromatography column.…”

mentioning

confidence: 99%

8‐Epi‐xanthatin induces the apoptosis of DU145 prostate carcinoma cells through signal transducer and activator of transcription 3 inhibition and reactive oxygen species generation

Lee

Choi

Yoon

et al. 2020

Phytotherapy Research

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Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in many human cancers. We tried to find STAT3 inhibitors from natural sources and found that Xanthium fruit extracts decreased phosphorylation of STAT3-Y705. 8-Epi-xanthatin (EXT) was isolated from the extracts. When DU145 cancer cells were treated with EXT, p-STAT3-Y705 was decreased with an IC 50 of 3.2 μM. EXT decreased the expression of STAT3 target genes, such as cyclin A, cyclin D1, and BCL-2, and induced PARP cleavage, indicating apoptotic cell death. Downregulation of EXT-induced p-STAT3-Y705 was rescued by pretreating DU145 cells with antioxidants, such as N-acetyl-L-cysteine (NAC), indicating that reactive oxygen species (ROS) were involved in the EXT-induced inhibition of STAT3 activation. Furthermore, we proved the association of EXT with STAT3 protein by using a drug affinity responsive target stability (DARTS) assay and a cellular thermal shift assay (CETSA). EXT inhibited proliferation of DU145 cells with a GI 50 of 6 μM and reduced tumor growth in mice xenografted with DU145 cells. Immunoblotting showed that phosphorylation of STAT3-Y705 was lower in EXT-treated tumor tissue than in control tissues. Collectively, we found that EXT binds to, and inhibits, STAT3 activation and could be a lead compound for anticancer therapy.

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Natural Sesquiterpene Lactones Enhance Chemosensitivity of Tumor Cells through Redox Regulation of STAT3 Signaling

Cited by 17 publications

References 153 publications

<p>Brevilin A, a Natural Sesquiterpene Lactone Inhibited the Growth of Triple-Negative Breast Cancer Cells via Akt/mTOR and STAT3 Signaling Pathways</p>

<p>Brevilin A, a Natural Sesquiterpene Lactone Inhibited the Growth of Triple-Negative Breast Cancer Cells via Akt/mTOR and STAT3 Signaling Pathways</p>

<p>PSAT1 Regulated Oxidation-Reduction Balance Affects the Growth and Prognosis of Epithelial Ovarian Cancer</p>

8‐Epi‐xanthatin induces the apoptosis of DU145 prostate carcinoma cells through signal transducer and activator of transcription 3 inhibition and reactive oxygen species generation

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