Triterpenoid Saponin AG8 from Ardisia gigantifolia stapf. Induces Triple Negative Breast Cancer Cells Apoptosis through Oxidative Stress Pathway

Triple-negative breast cancers (TNBCs) are associated with poor patient survival because of the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expressions. Our previous studies have shown that the triterpenoid saponin AG8 from Ardisia gigantifolia stapf. inhibits the proliferation of MDA-MB-231 cells. In this study, the effects of AG8 were further analyzed in different TNBC cell types: MDA-MB-231, BT-549, and MDA-MB-157 cells. AG8 inhibited the viability of MDA-MB-231, BT-549, and MDA-MB-157 cells in a dose-dependent manner and showed stronger cytotoxicity to African American (AA) and mesenchymal (M) subtypes than Caucasian (CA) and mesenchymal stem-like (MSL) subtypes, respectively. AG8 impaired the uptake of MitoTracker Red CMXRos by the mitochondria of TNBC cells in a dose-dependent manner, and this was recovered by N-acetyl-l-cysteine (NAC). AG8 affected GSH, SOD, and MDA levels of TNBC cells, but different TNBC subtypes had different sensitivities to AG8 and NAC. In addition, we found that AG8 increased the Bax/Bcl-2 ratio and the levels of cytoplasmic cytochrome c and significantly decreased phosphorylation of ERK and AKT in BT549 and MDA-MB-157 cells. AG8 elicited its anticancer effects through ROS generation, ERK and AKT activation, and by triggering mitochondrial apoptotic pathways in TNBC cells. AG8 had selective cytotoxic effects against the AA and M TNBC subtypes and markedly induced MDA-MB-157 (AA subtype) cell apoptosis through pathways that were not associated with ROS, which was different from the other two subtypes. The underlying mechanisms should be further investigated.

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Use of Proton Pump Inhibitors as Adjunct Treatment for Triple-Negative Breast Cancers. An Introductory Study

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j34608 ◽

2014 ◽

Vol 17 (3) ◽

pp. 439 ◽

Cited By ~ 29

Author(s):

Wayne Goh ◽

Inna Sleptsova-Freidrich ◽

Nenad Petrovic

Keyword(s):

Breast Cancer ◽

Cancer Treatment ◽

Cancer Cells ◽

Proton Pump ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Dependent Manner ◽

Breast Cancers ◽

Gastric Type ◽

Dose Dependent

PURPOSE: Triple negative breast cancers (estrogen, progesterone and human epidermal growth factor 2 (HER2) receptor-negative) are among the most aggressive forms of cancers with limited treatment options. Doxorubicin is one of the agents found in many of the current cancer treatment protocols, although its use is limited by dose-dependent cardiotoxicity. This work investigates one of the ways to suppress cancer growth by inhibiting tumor cell ability to remove acid accumulated during its metabolism by proton pump inhibitor esomeprazole (a drug with extensive clinical use) which could serve as an addition to doxorubicin therapy. METHODS: In this work, we have investigated growth suppression of triple-negative breast cancer cells MDA-MB-468 by esomeprazole and doxorubicin by trypan blue exclusion assay. Measurement of acidification of treated cancer cells was performed using intracellular pH-sensitive probe, BCECF-AM. Finally, expression of gastric type proton pump (H+/K+ ATPase, a target for esomeprazole) on MDA-MB-468 cells was detected by immunofluorescence and Western blotting. RESULTS: We have found that esomeprazole suppresses growth of triple-negative breast cancer cell in vitro in a dose-dependent manner through increase in their intracellular acidification. In contrast, esomeprazole did not have significant effect on non-cancerous breast epithelial MCF-10A cells. Esomeprazole increases doxorubicin effects suggesting that dual treatments might be possible. In addition, response of MDA-MB-468 cells to esomeprazole could be mediated by gastric type proton pump (H+/K+ ATPase) in cancer cells contrary to previous beliefs that this proton pump expression is restricted to parietal cells of the stomach epithelia. CONCLUSION: This study provides first evidence that adjunct use of esomeprazole in breast cancer treatment might be a possible to combat adverse effects of doxorubicin and increase its effectiveness. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Polydatin Attenuates Carbachol-induced Contraction of Guinea Pig Gallbladder

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:34-38 ◽

2019 ◽

Vol 18 (1) ◽

pp. 34-38

Author(s):

Chen Lei ◽

Pan Xiang ◽

Shen Yonggang ◽

Song Kai ◽

Zhong Xingguo ◽

...

Keyword(s):

Protein Kinase ◽

Guinea Pig ◽

Smooth Muscles ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Dependent Manner ◽

Underlying Mechanisms ◽

Dose Dependent

The aim of this study was to determine whether polydatin, a glucoside of resveratrol isolated from the root of Polygonum cuspidatum, warranted development as a potential therapeutic for ameliorating the pain originating from gallbladder spasm disorders and the underlying mechanisms. Guinea pig gallbladder smooth muscles were treated with polydatin and specific inhibitors to explore the mechanisms underpinning polydatin-induced relaxation of carbachol-precontracted guinea pig gallbladder. Our results shown that polydatin relaxed carbachol-induced contraction in a dose-dependent manner through the nitric oxide/cyclic guanosine monophosphate/protein kinase G and the cyclic adenosine monophosphate/protein kinase A signaling pathways as well as the myosin light chain kinase and potassium channels. Our findings suggested that there was value in further exploring the potential therapeutic use of polydatin in gallbladder spasm disorders.

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Nonylphenol Induces Apoptosis through ROS/JNK Signaling in a Spermatogonia Cell Line

International Journal of Molecular Sciences ◽

10.3390/ijms22010307 ◽

2020 ◽

Vol 22 (1) ◽

pp. 307

Author(s):

Hyun-Jung Park ◽

Ran Lee ◽

Hyunjin Yoo ◽

Kwonho Hong ◽

Hyuk Song

Keyword(s):

Molecular Mechanisms ◽

Mapk Signaling ◽

Ros Generation ◽

Dependent Manner ◽

Jnk Signaling ◽

Apoptosis Markers ◽

Testicular Size ◽

Spermatogonia Cell ◽

Induced Apoptosis ◽

Dose Dependent

Nonylphenol (NP) is an endocrine-disruptor chemical that negatively affects reproductive health. Testes exposure to NP results in testicular structure disruption and a reduction in testicular size and testosterone levels. However, the effects of NP on spermatogonia in testes have not been fully elucidated. In this study, the molecular mechanisms of NP in GC-1 spermatogonia (spg) cells were investigated. We found that cell viability significantly decreased and apoptosis increased in a dose-dependent manner when GC-1 spg cells were exposed to NP. Furthermore, the expression levels of the pro-apoptotic proteins increased, whereas anti-apoptosis markers decreased in NP-exposed GC-1 spg cells. We also found that NP increased reactive oxygen species (ROS) generation, suggesting that ROS-induced activation of the MAPK signaling pathway is the molecular mechanism of NP-induced apoptosis in GC-1 spg cells. Thus, NP could induce c-Jun phosphorylation; dose-dependent expression of JNK, MKK4, p53, and p38; and the subsequent inhibition of ERK1/2 and MEK1/2 phosphorylation. The genes involved in apoptosis and JNK signaling were also upregulated in GC-1 spg cells treated with NP compared to those in the controls. Our findings suggest that NP induces apoptosis through ROS/JNK signaling in GC-1 spg cells.

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Triple-Negative Breast Cancer: Adjuvant Therapeutic Options

Chemotherapy Research and Practice ◽

10.1155/2011/696208 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 17

Author(s):

Ayca Gucalp ◽

Tiffany A. Traina

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Growth Factor Receptor ◽

Progesterone Receptors ◽

Cytotoxic Chemotherapy ◽

Breast Cancers ◽

Targeted Agents ◽

Increased Risk ◽

Disproportionate Number

Triple-negative breast cancer (TNBC), a subtype distinguished by negative immunohistochemical assays for expression of the estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2(HER2) represents 15% of all breast cancers. Patients with TNBC generally experience a more aggressive clinical course with increased risk of disease progression and poorer overall survival. Furthermore, this subtype accounts for a disproportionate number of disease-related mortality in part due to its aggressive natural history and our lack of effective targeted agents beyond conventional cytotoxic chemotherapy. In this paper, we will review the epidemiology, risk factors, prognosis, and the molecular and clinicopathologic features that distinguish TNBC from other subtypes of breast cancer. In addition, we will examine the available data for the use of cytotoxic chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents.

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Classical Cyclophosphamide, Methotrexate, and Fluorouracil Chemotherapy Is More Effective in Triple-Negative, Node-Negative Breast Cancer: Results From Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.25.9549 ◽

2010 ◽

Vol 28 (18) ◽

pp. 2966-2973 ◽

Cited By ~ 102

Author(s):

Marco Colleoni ◽

Bernard F. Cole ◽

Giuseppe Viale ◽

Meredith M. Regan ◽

Karen N. Price ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Triple Negative ◽

Alkylating Agents ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Her2 Positive ◽

Node Negative ◽

Tumor Subtypes ◽

Node Negative Breast Cancer

Purpose Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents. Patients and Methods Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present. Results Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor–absent, and endocrine receptor–present subtypes. No clear chemotherapy benefit was observed in endocrine receptor–present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor–present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor–absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor–present disease). Conclusion The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.

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Drug-Induced Resistance and Phenotypic Switch in Triple-Negative Breast Cancer Can Be Controlled via Resolution and Targeting of Individualized Signaling Signatures

Cancers ◽

10.3390/cancers13195009 ◽

2021 ◽

Vol 13 (19) ◽

pp. 5009

Author(s):

Swetha Vasudevan ◽

Ibukun A. Adejumobi ◽

Heba Alkhatib ◽

Sangita Roy Chowdhury ◽

Shira Stefansky ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Growth Factor Receptor ◽

Patient Specific ◽

Network Structures ◽

Breast Cancers ◽

Drug Induced ◽

Tcga Dataset

Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancers which is treated mainly with chemotherapy and radiotherapy. Epidermal growth factor receptor (EGFR) was considered to be frequently expressed in TNBC, and therefore was suggested as a therapeutic target. However, clinical trials of EGFR inhibitors have failed. In this study, we examine the relationship between the patient-specific TNBC network structures and possible mechanisms of resistance to anti-EGFR therapy. Using an information-theoretical analysis of 747 breast tumors from the TCGA dataset, we resolved individualized protein network structures, namely patient-specific signaling signatures (PaSSS) for each tumor. Each PaSSS was characterized by a set of 1–4 altered protein–protein subnetworks. Thirty-one percent of TNBC PaSSSs were found to harbor EGFR as a part of the network and were predicted to benefit from anti-EGFR therapy as long as it is combined with anti-estrogen receptor (ER) therapy. Using a series of single-cell experiments, followed by in vivo support, we show that drug combinations which are not tailored accurately to each PaSSS may generate evolutionary pressure in malignancies leading to an expansion of the previously undetected or untargeted subpopulations, such as ER+ populations. This corresponds to the PaSSS-based predictions suggesting to incorporate anti-ER drugs in certain anti-TNBC treatments. These findings highlight the need to tailor anti-TNBC targeted therapy to each PaSSS to prevent diverse evolutions of TNBC tumors and drug resistance development.

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Prognostic Evaluation of Epidermal Growth Factor Receptor (EGFR) Genotype and Phenotype Parameters in Triple-negative Breast Cancers

Cancer Genomics & Proteomics ◽

10.21873/cgp.20030 ◽

2017 ◽

Vol 14 (3) ◽

pp. 181-195 ◽

Cited By ~ 13

Author(s):

SOFIA LEVVA ◽

VASSILIKI KOTOULA ◽

IOANNIS KOSTOPOULOS ◽

KYRIAKI MANOUSOU ◽

CHRISTOS PAPADIMITRIOU ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Triple Negative ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Prognostic Evaluation ◽

Epidermal Growth

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Practical Approach to Triple-Negative Breast Cancer

Journal of Oncology Practice ◽

10.1200/jop.2017.022632 ◽

2017 ◽

Vol 13 (5) ◽

pp. 293-300 ◽

Cited By ~ 24

Author(s):

Vijayakrishna K. Gadi ◽

Nancy E. Davidson

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Hormone Receptors ◽

Triple Negative ◽

Early Stage ◽

Management Strategies ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Epidermal Growth ◽

Proven Method

Triple negative is a term applied to breast cancers that do not meaningfully express the estrogen or progesterone hormone receptors or overexpress the human epidermal growth factor receptor 2 tyrosine kinase. At present, the only proven method for systemic management of triple-negative breast cancer for both early-stage and metastatic settings is cytotoxic chemotherapy. Here, we provide a comprehensive review of management strategies that are best supported by available data. We also review recent advances most likely to affect treatment of triple-negative breast cancer in the coming years with particular emphasis on targeted agents, biologics, and immunotherapy.

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CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1

Cell Death and Disease ◽

10.1038/s41419-021-04114-8 ◽

2021 ◽

Vol 12 (9) ◽

Author(s):

Hong Luo ◽

Zhicheng Zhou ◽

Shan Huang ◽

Mengru Ma ◽

Manyu Zhao ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Triple Negative Breast Cancer ◽

Fatty Acid Synthase ◽

Triple Negative ◽

Trichostatin A ◽

Affinity Purification ◽

Negative Regulator ◽

Dependent Manner ◽

Breast Cancers

AbstractFailures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.

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Emodin promotes apoptosis of human endometrial cancer through regulating the MAPK and PI3K/ AKT pathways

Open Life Sciences ◽

10.1515/biol-2018-0058 ◽

2019 ◽

Vol 13 (1) ◽

pp. 489-496 ◽

Cited By ~ 2

Author(s):

Jun Jiang ◽

Nanyang Zhou ◽

Pian Ying ◽

Ting Zhang ◽

Ruojia Liang ◽

...

Keyword(s):

Endometrial Cancer ◽

Signaling Pathways ◽

Tumor Development ◽

Mapk Signaling ◽

Dependent Manner ◽

Western Blot Assay ◽

Anti Oxidant ◽

Underlying Mechanisms ◽

Induced Apoptosis ◽

Dose Dependent

AbstractEmodin, a major component of rhubarb, has anti-tumor effects in a variety of cancers, influencing multiple steps of tumor development through modulating several signaling pathways. The aim of this study is to examine the effect of emodin on cell apoptosis and explore the underlying mechanisms in human endometrial cancer cells. Here we report that emodin can inhibit KLE cell proliferation and induce apoptosis in a time- and dose-dependent manner. Western blot assay found that emodin was involved in MAPK and PI3K/Akt signaling pathways. Specifically, emodin significantly suppressed the phosphorylation of AKT, and enhanced the phosphorylation of MAPK pathways. Furthermore, the generation of reactive oxygen species (ROS) was up-regulated in KLE cells upon treatment with emodin, while the anti-oxidant agent N-acetyl cysteine (NAC) can inhibit emodin-induced apoptosis and promote the activation of AKT and Bcl-2. Taken together, we revealed that emodin may induce apoptosis in KLE cells through regulating the PI3K/AKT and MAPK signaling pathways, indicating the importance of emodin as an anti-tumor agent.

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