Apigenin overcomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells

Seo, Hye‐Sook; Ku, Jin Mo; Choi, Ha Na; Woo, Jong Kyu; Lee, Byung‐Hoon; Kim, Doh Sun; Song, Hyun Jong; Jang, Bo‐Hyoung; Shin, Yong Cheol; Ko, Seong‐Gyu

doi:10.3892/or.2017.5752

Cited by 57 publications

(30 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transcription factors can bind to the binding sites of the promoter region of genes, and initiate gene transcription, having important regulatory functions ( 28 , 29 ). In cancer, transcription factors are often able to initiate transcription of multiple downstream oncogenes or tumor-suppressor genes, thereby inducing a cascade of responses that regulate cell proliferation, invasion, metastasis, differentiation, drug resistance, and apoptosis ( 30 , 31 ). Studies show that multiple transcription factors are closely related to the recurrence and metastasis of colon cancer.…”

Section: Discussionmentioning

confidence: 99%

FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer

et al. 2018

View full text Add to dashboard Cite

The present study determined the expression and biological functions of FOXA2 gene in colon cancer in tissues, cells and animals. A total of 66 patients with colon cancer were included in the present study. Using The Human Protein Atlas database, expression and distribution of FOXA2 in colon cancer tissues were analyzed. Using immunohistochemistry, the expression and distribution of FOXA2 in colon cancer cells were studied. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression of FOXA2 mRNA in colon cancer tissues. Following in vitro transfection with FOXA2 interference sequence (siR-FOXA2), the proliferation, cell cycle, migration and invasion of colon cancer HCT116 and HT29 cells were investigated using Cell Counting Kit-8 assay, flow cytometry, and Transwell assay, respectively. Furthermore, flow cytometry was used to determine apoptosis of HCT116 and HT29 cells. Western blotting was used to determine the expression of epithelial mesenchymal transition (EMT) proteins, E-Cadherin and Vimentin. Laser scanning confocal microscopy was performed to observe the cytoskeleton in HCT116 and HT29 cells. Results indicated tumorigenesis of colon cancer cells in nude mice. In addition, the expression of FOXA2 in colon cancer tissues was elevated and associated with the metastasis and clinical staging of colon cancer. Notably, inhibition of FOXA2 reduced the proliferation of colon cancer cells in vitro and reduced expression of FOXA2 was able to decrease the migration and invasion abilities of colon cancer cells. Furthermore, FOXA2 promoted EMT, inhibited apoptosis and enhanced the invasion ability of colon cancer cells. Decreased expression of FOXA2 inhibited tumorigenesis of colon cancer cells in nude mice. To conclude, the present study demonstrated that the expression of FOXA2 in colon cancer tissues was elevated and associated with the metastasis and clinical staging of colon cancer. As an oncogene, FOXA2 may promote the proliferation, migration and invasion and EMT in colon cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…CYP1B1 inhibitors have also been shown to enhance the chemotherapeutic effects of DOX in several cancer cell lines including lung cancer [192][193][194], breast cancer [195][196][197][198][199][200][201], liver cancer [201][202][203][204], glioblastoma [205], prostate cancer [206], colorectal cancer [207,208], gastric cancer [209], and leukemia [210,211]. Importantly, several inhibitors have also been shown to overcome DOX resistance in DOX-resistant cancer cell lines [209,210,[212][213][214][215][216][217].…”

Section: Chemosensitizing Effects Of Cyp1b1 Inhibitorsmentioning

confidence: 99%

“…Inhibition of CYP1B1 may interplay with these pathways leading to the chemo-sensitizing effects. [194] Isorhamnetin 17 [219] Protection from chronic DOX-induced cardiotoxicity in vivo in rats and in vitro in H9c2 cells [201] Potentiates DOX-induced toxicity in MCF-7, HepG2, and Hep2 cancer cells [201] Chrysin 24-270 [219,220] Protection from acute and chronic DOX-induced cardiotoxicity in vivo in rats [222,223] Enhanced cytotoxicity of DOX in a spheroid culture model of human lung squamous cell carcinoma [224], BEL-7402/ADM [225], lung cancer A549 cells [192], and human non-small-cell lung cancer cell lines [193] Apigenin 25 [219] Attenuated chronic DOX-induced cardiotoxicity in in vivo in rats and in vitro in rat cardiomyocytes [186][187][188] Augmented the cytotoxic effect of DOX against HepG2 cells [203], and DOX-resistant hepatocellular carcinoma cell line BEL-7402/ADM [204,218,226] Reverse chemo-resistance to DOX in DOX-resistant breast cancer cells (MCF-7/ADR) [198] Kaempferol 47 [219] Protected from chronic DOX-induced cardiotoxicity in vivo in rats and in vitro in H9c2 cells [227] Potentiated the cytotoxic effect of DOX in glioblastoma cells [205] Quercetin 77 [219] Protected rat and human cardiomyocytes and H9c2 cells from DOX-induced toxicity in vitro [176,188,189,199,228]. Protected from chronic DOX in rats [190,229] and mice [185] in vivo.…”

Section: Chemosensitizing Effects Of Cyp1b1 Inhibitorsmentioning

confidence: 99%

CYP1B1 as a therapeutic target in cardio-oncology

2020

View full text Add to dashboard Cite

Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of evidence suggesting that inhibition of the cytochrome P450 1B1 enzyme (CYP1B1) can be a promising therapeutic strategy that has the potential to prevent cancer treatment-induced cardiovascular complications without reducing their anti-cancer effects. CYP1B1 is an extrahepatic enzyme that is expressed in cardiovascular tissues and overexpressed in different types of cancers. A growing body of evidence is demonstrating a detrimental role of CYP1B1 in both cardiovascular diseases and cancer, via perturbed metabolism of endogenous compounds, production of carcinogenic metabolites, DNA adduct formation, and generation of reactive oxygen species (ROS). Several chemotherapeutic agents have been shown to induce CYP1B1 in cardiovascular and cancer cells, possibly via activating the Aryl hydrocarbon Receptor (AhR), ROS generation, and inflammatory cytokines. Induction of CYP1B1 is detrimental in many ways. First, it can induce or exacerbate cancer treatment-induced cardiovascular complications. Second, it may lead to significant chemo/radio-resistance, undermining both the safety and effectiveness of cancer treatments. Therefore, numerous preclinical studies demonstrate that inhibition of CYP1B1 protects against chemotherapy-induced cardiotoxicity and prevents chemo- and radio-resistance. Most of these studies have utilized phytochemicals to inhibit CYP1B1. Since phytochemicals have multiple targets, future studies are needed to discern the specific contribution of CYP1B1 to the cardioprotective and chemo/radio-sensitizing effects of these phytochemicals.

show abstract

“…Apigenin is a natural compound which has the capacity to antagonize several mitigating events in human tumor development and tumor immune evasion. These include the capability to reduce inflammation, inhibit casein kinase 2 (CK2), matrix metalloproteinases 9 and 1, protein kinase C (18), cytochrome P450 1A1 (19) topoisomerase I (20) tumor growth factors (21), CCL2-induced release by TNFαactivated breast cancer (22) and blockade of drug resistanceassociated extrusion pumps (23,24). In the current study, we expand on our previous work by evaluating the effects of apigenin on TNFα-treated MDA-MB-231 cells (22) by analyzing the whole transcriptome.…”

mentioning

confidence: 99%

Whole Transcriptomic Analysis of Apigenin on TNFα Immuno-activated MDA-MB-231 Breast Cancer Cells

Bauer

Mazzio

Soliman

2019

Cancer Genomics Proteomics

View full text Add to dashboard Cite

Background: Triple-negative breast cancer is categorized by a lack of hormone receptors, inefficacy of antiestrogen or aromatase inhibitor chemotherapies and greater mortality rates in African American populations. Advancedstage breast tumors have a high concentration of tumor necrosis factor-α (TNFα) throughout the tumor/stroma milieu, prompting sustained release of diverse chemokines (i.e. CC motif chemokine ligand 2 (CCL2)/CCL5). These potent chemokines can subsequently direct mass infiltration of leukocyte sub-populations to lodge within the tumor, triggering a loss of tumor immune surveillance and subsequent rapid tumor growth. Previously, we demonstrated that in the MDA-MB-231 TNBC cell line, TNFα evoked a rise in immune signaling proteins: CCL2, granulocyte macrophage colonystimulating factor, interleukin (IL)1α, IL6 and inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKε) all of which were attenuated by apigenin, a dietary flavonoid found in chamomile and parsley. Materials and Methods: The present work elucidates changes evoked by TNFα in the presence or absence of apigenin by examining the entire transcriptome for mRNA and long intergenic non-coding RNA with Affymetrix Hugene-2.1_ST human microarrays. Differential geneexpression analysis was conducted on 48,226 genes. Results: TNFα caused up-regulation of 75 genes and down-regulation of 10. Of these, apigenin effectively down-regulated 35 of the 75 genes which were up-regulated by TNFα. These findings confirm our previous work, specifically for the TNFα-evoked spike in IL1A vs. untreated controls [+21-fold change (FC), p<0.0001] being attenuated by apigenin in the presence of TNFa (−15 FC vs. TNFα, p<0.0001). Similar trends were seen for apigenin-mediated down-regulation of TNFα-up-regulated transcripts: IKBKE (TNFα: 4.55 FC vs. control, p<0.001; and TNFα plus apigenin: −4.92 FC, p<0.001), CCL2 (2.19 FC, p<0.002; and −2.12 FC, p<0.003), IL6 (3.25 FC, p<0.020; and −2.85 FC, p<0.043) and CSF2 (TNFα +6.04 FC, p<0.001; and −2.36 FC, p<0.007). In addition, these data further establish more than a 65% reduction by apigenin for the following transcripts which were also up-regulated by TNFα: cathepsin S (CTSS), complement C3 (C3), laminin subunit gamma 2 (LAMC2), (TLR2), toll-like receptor 2 G protein-coupled receptor class C group 5 member B (GPRC5B), contactin-associated protein 1 (CNTNAP1), claudin 1 (CLDN1), nuclear factor of activated T-cells 2 (NFATC2), C-X-C motif chemokine ligand 10 (CXCL10), CXCL11, interleukin 1 receptor-associated kinase 3 (IRAK3), nuclear receptor subfamily 3 group C member 2 (NR3C2), interleukin 32 (IL32), IL24, slit guidance ligand 2 (SLIT2), transmembrane protein 132A (TMEM132A), TMEM171, signal transducing adaptor family member 2 (STAP2), mixed lineage kinase domain-like pseudokinase (MLKL), kinase insert domain receptor (KDR), BMP-binding endothelial regulator (BMPER), and kelch-like family member 36 (KLHL36). Conclusion: There is a possible therapeutic role for apigenin in down-regulating diverse genes associated...

show abstract

Apigenin overcomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells

Cited by 57 publications

References 42 publications

FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer

FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer

CYP1B1 as a therapeutic target in cardio-oncology

Whole Transcriptomic Analysis of Apigenin on TNFα Immuno-activated MDA-MB-231 Breast Cancer Cells

Contact Info

Product

Resources

About