Brevilin A Induces Cell Cycle Arrest and Apoptosis in Nasopharyngeal Carcinoma

Li, Rui; Zhao, Qian; Lin, Yi; Lee, Chi‐Sing; Tai, William; Chen, Sibao

doi:10.3389/fphar.2019.00594

Cited by 32 publications

(20 citation statements)

References 42 publications

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“…Brv-A induced G 2 /M phase arrest in MCF-7 cells in dose-dependent fashion which was consistent with previous published findings. 19 Sesquiterpene lactones are well-known compounds for inducing apoptotic cell death in various cancer cell types. 44 These compounds have also been confirmed to induce ROS generation.…”

Section: Discussionmentioning

confidence: 99%

Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells

Saleem

Nisar

Alshwmi

et al. 2020

OTT

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Breast cancer is the most common malignancy among women across the globe. Despite concerted efforts to improve the prevailing treatment modalities, the overall prognosis of breast cancer remains unsatisfactory. Recently, antiproliferative activity of Brevilin A (Brv-A), a sesquiterpene lactone compound of Centipeda minima, has been unveiled in various cancer types. Here, we have explored anticancer activity of Brv-A in MCF-7 breast carcinoma cells by targeting various pathways. Materials and Methods: Cell proliferation rate was determined by CCK-8 and clonogenic assay. Cellular morphological changes were observed under phase contrast microscope while calcein-AM and PI was used for live/dead assay. Cell cycle assay was performed by flow cytometry. Apoptotic cell percentage was determined by Hoechst 33258 staining and flow cytometric analysis. ROS generation and mitochondrial membrane potential were measured using commercially available kits while protein expression was measured by Western blotting. Results: In our study, Brv-A exerted antiproliferative effect through mitotic arrest at G 2 /M phase of cell cycle and induced apoptosis in MCF-7 cells in a dose-dependent manner. Induction of apoptosis by Brv-A was found to be associated with ROS generation by targeting NOX2 and NOX3, mitochondrial dysfunction (MMP dissipation and Bcl-2 family proteins modulation), DNA fragmentation, JNK and p38 MAPK activation, endoplasmic reticulum (ER) stress by increasing Bip/GRP78, ATF4 and CHOP protein expressions and inhibition of STAT3 activation via decreased phosphorylation of JAK2 and SRC. Pretreatment of NAC, a ROS scavenger, partially reversed the aforesaid cellular events indicating ROS generation as the primary event to modulate cellular targets for induction of apoptosis. Besides, Brv-A has also been documented for inhibition of cell migration via decrease in COX-2 and MMP-2 expression. Conclusion: Taken together, Brv-A induces G 2 /M phase arrest, ROS-dependent apoptosis, ER stress, mitochondrial dysfunction and inhibits STAT3 activation in MCF-7 cells signifying it to be one of the potential anticancer therapeutics in future.

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Section: Discussionmentioning

confidence: 99%

Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells

Saleem

Nisar

Alshwmi

et al. 2020

OTT

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“…The whole plant has been employed as a TCM for millennia and is commonly treatment for indications such as rhinitis, sinusitis, cough, headache, swelling, and allergy (11). Phytochemical research has demonstrated CM mainly contain phenolic acids (e.g., isochlorogenic acid A and isochlorogenic acid C), flavonoids, and sesquiterpene lactones [e.g., Brevilin A, Arnicolide D; (12)(13)(14)(15)(16)]. Reports suggest that Centipeda minima extracts (CME) possess anti-inflammatory (17), anti-bacterial (18,19), and anti-allergic (20) effects.…”

Section: Introductionmentioning

confidence: 99%

“…Reports suggest that Centipeda minima extracts (CME) possess anti-inflammatory (17), anti-bacterial (18,19), and anti-allergic (20) effects. Previous studies have demonstrated the anti-cancer effects of CME, and compounds extracted from CM, in various cancers including nasopharyngeal carcinoma (13,14,21,22), leukemia (23), glioblastoma (24), lung cancer (25), and colon cancer (26), however, the effects of CME on breast cancer have to date, not been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Anti-cancer Activity of Centipeda minima Extract in Triple Negative Breast Cancer via Inhibition of AKT, NF-κB, and STAT3 Signaling Pathways

et al. 2020

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Breast cancer is the most commonly diagnosed cancer in females worldwide. Estimates from the World Health Organization (WHO) International Agency for Research on Cancer, suggest that globally, there were around 2.1 million new breast cancer cases and 627,000 deaths due to breast cancer in 2018. Among the subtypes of breast cancer, triple negative breast cancer (TNBC) is the most aggressive and carries the poorest prognosis, largest recurrence, and lowest survival rate. Major treatment options for TNBC patients are mainly constrained to chemotherapy, which can be accompanied by severe side effects. Therefore, development of novel and effective anti-cancer drugs for the treatment of TNBC are urgently required. Centipeda minima is a well-known traditional Chinese herbal medicine that has historically been used to treat rhinitis, sinusitis, relieve pain, and reduce swelling. Recent studies have shown that Centipeda minima exhibited efficacy against certain cancers, however, to date, no studies have been conducted on its effects in breast cancer. Here, we aimed to investigate the anti-cancer activity of the total extract of Centipeda minima (CME), and its underlying mechanism, in TNBC. In MDA-MB-231, we found that CME could significantly reduce cell viability and proliferation, induce apoptosis and inhibit cancer cell migration and invasion, in a dose and time-dependent manner. We showed that CME may potentially act via inhibition of multiple signaling pathways, including the EGFR, PI3K/AKT/mTOR, NF-κB, and STAT3 pathways. Treatment with CME also led to in vitro downregulation of MMP-9 activity and inhibition of metastasis. Further, we demonstrated that CME could significantly reduce tumor burden in MDA-MB-231 xenograft mice, without any appreciable side effects. Based on our findings, CME is a promising candidate for development as a therapeutic with high efficacy against TNBC.

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“…et Aschers., and has been reported to exhibit anti-viral and anti-cancer effects, 5,6 in cancers such as colon carcinoma, glioblastoma and nasopharyngeal carcinoma. [7][8][9] However, the effects of BA on TNBC have not yet been demonstrated. Thus, in this study, we investigated the in vitro and in vivo anti-cancer effects of BA in TNBC.…”

Section: Introductionmentioning

confidence: 99%

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

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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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Brevilin A Induces Cell Cycle Arrest and Apoptosis in Nasopharyngeal Carcinoma

Cited by 32 publications

References 42 publications

<p>Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells</p>

<p>Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells</p>

Anti-cancer Activity of Centipeda minima Extract in Triple Negative Breast Cancer via Inhibition of AKT, NF-κB, and STAT3 Signaling Pathways

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

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