EGCG Enhanced the Anti-tumor Effect of Doxorubicine in Bladder Cancer via NF-κB/MDM2/p53 Pathway

Abstract

Doxorubicin (DOX), the first-line chemotherapy for bladder cancer, usually induces side effects. We previously demonstrated that green tea polyphenol EGCG had potent anti-tumor effect in bladder cancer via down regulation of NF-κB. This study aimed to investigate the additive/synergistic effect EGCG and DOX against bladder cancer. Our results demonstrated that the combined use of DOX and EGCG inhibited T24 and SW780 cell proliferation. EGCG enhanced the apoptosis induction effect of DOX in both SW780 and T24 cells and resulted in significant differences. Besides, EGCG promoted the inhibitory effect of DOX against bladder cancer cell migration. In addition, the in vivo results demonstrated that DOX in combination with EGCG showed the most potent anti-tumor effects among DOX, EGCG and DOX+EGCG treatment groups. Further mechanistic studies determined that the combination of DOX and EGCG inhibited phosphorylated NF-κB and MDM2 expression, and up-regulated p53 expression in tumor, as assessed by western blot and immunohistochemistry. Western blot in SW780 cells also confirmed that the combined use of EGCG and DOX caused significant increase in p53, p21, and cleaved-PARP expression, and induced significant inhibition in phosphorylated NF-κB and MDM2. When NF-κB was inhibited, the expression of p53 and p-MDM2 were changed, and the combination of DOX and EGCG showed no obvious effect in transwell migration and cell viability. In conclusion, the novel application of chemotherapy DOX and EGCG demonstrated potent anti-tumor, anti-migration and anti-proliferation effects against bladder cancer. EGCG enhanced the anti-tumor effect of DOX in bladder cancer via NF-κB/MDM2/p53 pathway, suggesting the potential clinical application against bladder cancer patients.

Epigallocatechin Gallate Restrains Angiogenesis and Glycolysis in Colorectal Cancer via the Circular Ribonucleic Acid Actin Gamma 2/Micro Ribonucleic Acid-370-5p Pathway

“…Therefore, there is an urgent need to develop new treatments for CRC. EGCG is the most biologically active polyphenol in green tea and takes on multiple roles in cancer prevention and treatment [10] . A previous study clarifies EGCG induces CRC cell apoptosis by inducing endoplasmic reticulum stress through the Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK)/ phosphorylated eukaryotic translation Initiation Factor 2 Alpha (p-eIF2α)/Activating Transcription Factor 4 (ATF4) and Inositol-Requiring Enzyme 1 α (IRE1α) pathways [23] .…”

“…For example, in Breast Cancer (BC), EGCG refrains cell proliferation and differentiation, induces apoptosis and targets angiogenesis by depressing Vascular Endothelial Growth Factor (VEGF) transcription [9] . In bladder cancer, EGCG enhances the sensitivity of bladder cancer cells to the chemotherapeutic drug doxorubicin [10] . Meanwhile, EGCG enhances the sensitivity of CRC cells to the cancer chemotherapeutic drug 5-FU by restraining the Glucose Regulated Protein 78 (GRP78)/ Nuclear Factor Kappa B (NF-κB)/micro Ribonucleic Acid (miR)-155-5p/Multidrug Resistance Protein 1 (MDR1) pathway [11] .…”

Global Trends in Research of Treatment on Bladder Cancer with Chinese Medicine Monomer from 2000 to 2021: A Bibliometric Analysis

“…Multiple molecules could enhance bladder cancer cell migration, invasion, and proliferation by activating NF- κ B signaling [ 27 , 28 ]. Some compounds can also inhibit bladder cancer by inhibiting NF-kappa B [ 25 , 26 , 29 ]. This study shows that quercetin is the most studied monomer compound in all traditional Chinese medicine.…”

Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy

“…Polyphenol quercetin is another anticancer compound that works synergistically with paclitaxel ( 349 , 350 ), tamoxifen ( 351 ), cisplatin ( 352 , 353 ), adriamycin ( 354 ), and gemcitabine ( 355 ) to suppress the growth of various models of cancer via enhanced ROS production, cell cycle arrest, ER stress, and apoptosis. Similarly, various studies have reported the advantages of adding EGCG to enhance the antitumor activity of sunitinib, irinotecan, doxorubicin, gemcitabine, and cisplatin against human lung (A549, H460, and H1975) ( 356 , 357 ), colorectal (HCT116 and RKO) ( 358 ), bladder (SW780 and T24) ( 359 ), pancreatic (MIA PaCa-2 and Panc-1) ( 360 ), and ovarian (OVCAR3 and SKOV3) ( 361 ) cancer cells, respectively. The results emphasized that EGCG could potentate the antineoplastic activity of the aforementioned drugs by increasing the sensitivity of the cancer cells, thereby enhancing their antiproliferative activity, damaging DNA, interfering with the NF-κB/MDM2/p53 pathway, inhibiting Akt, and elevating copper transporter 1 (CTR1).…”