Gallic acid inhibition of Src-Stat3 signaling overcomes acquired resistance to EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer

Phan, Ai N.H.; Hua, Tuyen N M; Kim, Min kyu; Vo, Vu T.A.; Choi, Jong Whan; Kim, Hyun Won; Rho, Jin Kyung; Kim, Ki Woo; Jeong, Yangsik

doi:10.18632/oncotarget.10581

Cited by 36 publications

(28 citation statements)

References 40 publications

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“…Thus, a targeted study focused on using natural compounds is essential to achieve more effective anticancer treatment. Many studies have investigated a phenolic natural compound, gallic acid, that acts as an anticancer agent against various cancers [16,17,19,20]. Nevertheless, these studies did not identify where the target position of GA is against various cancer cells or did they reveal detailed molecular mechanisms underlying the anticancer effects of GA in cancer cell death.…”

Section: Discussionmentioning

confidence: 99%

“…However, the main interest in GA and its derivatives surrounds its anticancer activity. Previous studies have revealed that GA effectively induces selective apoptosis in various cancer cells, including HeLa, HCT-15, SH-SY5Y, and NSCLC cells [16][17][18][19] and inhibits proliferation and migration via regulating fatty acid synthase in TSGH-8301 cells [20]. Recent studies also revealed potential anticancer effects of GA is due to its ability to inhibit cell proliferation and to induce apoptosis in vivo [21,22].…”

Section: Introductionmentioning

confidence: 99%

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The Inhibitory Mechanisms of Tumor PD-L1 Expression by Natural Bioactive Gallic Acid in Non-Small-Cell Lung Cancer (NSCLC) Cells

Kang

et al. 2020

Cancers

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Non-small-cell lung cancer (NSCLC) is the most common lung cancer subtype and accounts for more than 80% of all lung cancer cases. Epidermal growth factor receptor (EGFR) phosphorylation by binding growth factors such as EGF activates downstream prooncogenic signaling pathways including KRAS-ERK, JAK-STAT, and PI3K-AKT. These pathways promote the tumor progression of NSCLC by inducing uncontrolled cell cycle, proliferation, migration, and programmed death-ligand 1 (PD-L1) expression. New cytotoxic drugs have facilitated considerable progress in NSCLC treatment, but side effects are still a significant cause of mortality. Gallic acid (3,4,5-trihydroxybenzoic acid; GA) is a phenolic natural compound, isolated from plant derivatives, that has been reported to show anticancer effects. We demonstrated the tumor-suppressive effect of GA, which induced the decrease of PD-L1 expression through binding to EGFR in NSCLC. This binding inhibited the phosphorylation of EGFR, subsequently inducing the inhibition of PI3K and AKT phosphorylation, which triggered the activation of p53. The p53-dependent upregulation of miR-34a induced PD-L1 downregulation. Further, we revealed the combination effect of GA and anti-PD-1 monoclonal antibody in an NSCLC-cell and peripheral blood mononuclear–cell coculture system. We propose a novel therapeutic application of GA for immunotherapy and chemotherapy in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Inhibitory Mechanisms of Tumor PD-L1 Expression by Natural Bioactive Gallic Acid in Non-Small-Cell Lung Cancer (NSCLC) Cells

Kang

et al. 2020

Cancers

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“…The authors concluded that the main effects were due to its antioxidant and antiinflammatory properties, and also by the induction of apoptosis [29]. It has been reported, for example, that gallic acid increases Bax protein expression and decreases Bcl-2 protein expression [30], suppresses Src-Stat3dependent signaling [31], reduces expression levels of RNAm of genes related to cell migration [32] and induces ATM-Chk2 activation [33].…”

Section: Discussionmentioning

confidence: 99%

Gallic acid produces hepatoprotection by modulating EGFR expression and phosphorylation in induced preneoplastic liver foci in rats

Reyes‐Esparza¹,

Escutia-Gutiérrez²,

Q.B.P.³

et al. 2019

OJGH

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Research Article OJGH (2019) 2:27 Gallic acid produces hepatoprotection by modulating EGFR expression and phosphorylation in induced preneoplastic liver foci in rats The purpose of this study was to analyze the role of gallic acid as liver protector and identify its role in the regulation of EGFR expression and phosphorylation in induced preneoplastic liver lesions in rats. Male Wistar rats were randomly divided into four groups. (1) Control; (2) animals receiving gallic acid (AG) 50 mg/ kg v.o. for 8 weeks; (3) animals with preneoplasia (P) induced by a single dose of diethylnitrosamine 200 mg/kg i.p. (DEN) and two weeks after a single dose of carbon tetrachloride 2 mL/kg i.p. (CCl4); and (4) animals with preneoplasia treated with GA during 8 weeks. In order to evaluate GA hepatoprotection on preneoplastic lesions, we performed histological examination of liver tissue using H&E staining as well as an immunohistochemical analysis for PCNA. To evaluate the effect of GA on EGFR expression and phosphorylation, we performed an immunohistochemical and western blot analysis. The results indicated that GA significantly decreased EGFR expression and pY1068 EGFR phosphorylation in animals with preneoplastic lesions. GA significantly decreased PCNA expression in animals with preneoplastic lesions, suggesting it may work as an antiproliferative agent. Additionally, GA improved the architecture and organization of liver tissue and significantly decreased serum AST, ALT and FA, which are indicators of hepatocellular damage. By histopathological and immunohistochemical analysis we demonstrated an improvement in liver morphology, a reduction of preneoplastic liver foci and a reduction of cell proliferation, as well as an improvement on liver functionality. In conclusion, GA produces hepatoprotection by modulating EGFR expression and phosphorylation in preneoplastic lesions.

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“…Another mechanism involved in gallic acid overcoming MDR is the inhibition of Src/STAT3-mediated signaling and the decrease in the expression of STAT3-regulated tumor-promoting genes, therefore inducing apoptosis and cell cycle arrest. It is well known that activation of STAT3 signaling pathway is associated with resistance to tyrosine kinase inhibitors, which are frequently used in lung cancer treatment [221].…”

Section: Hydroxy-benzoic Acidsmentioning

confidence: 99%

Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer

Costea

Vlad

Miclea

et al. 2020

IJMS

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The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.

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Gallic acid inhibition of Src-Stat3 signaling overcomes acquired resistance to EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer

Cited by 36 publications

References 40 publications

The Inhibitory Mechanisms of Tumor PD-L1 Expression by Natural Bioactive Gallic Acid in Non-Small-Cell Lung Cancer (NSCLC) Cells

The Inhibitory Mechanisms of Tumor PD-L1 Expression by Natural Bioactive Gallic Acid in Non-Small-Cell Lung Cancer (NSCLC) Cells

Gallic acid produces hepatoprotection by modulating EGFR expression and phosphorylation in induced preneoplastic liver foci in rats

Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer

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