Investigating the Role of Quercetin in Increasing the Rate of Cisplatin-Induced Apoptosis Via the NF-κB Pathway in MG-63 Cancer Cells

Abstract

Introduction Numerous studies suggest that the co-treatment of chemotherapeutic agents with flavonoids such as Quercetin (Que) may enhance tumor cells’ susceptibility to these agents. Hence, in the current study, we investigated Que’s role in combination with Cisplatin to promote cell apoptosis by focusing on the NF-κB signaling pathway in the osteosarcoma cell lines.

Methods The Que, Cisplatin, and their combination’s general cytotoxicity effects were evaluated using an MTT assay for 72 hrs. The protein expression levels of NF-κB were detected by an enzyme-linked immunosorbent assay (ELISA) Kit. Flow cytometry was used to evaluate cell apoptosis.

Results Que considerably elevated the cytotoxicity of Cisplatin (P<0.05). Que also dramatically down-regulated the expression levels of NF-κB in MG-63 cells compared to mono-treatment (P<0.05). Besides, Que promotes cisplatin-induced apoptosis in MG-63 cells.

Conclusion Our study’s findings provide an exact point in the field of adjuvant therapy in osteosarcoma. In other words, this study could provide new insights into a better understanding of the role of Que in elevating cisplatin-induced apoptosis with NF-κB down-regulation.

Key words

Osteosarcoma - Cisplatin - Quercetin - Apoptosis - NF-κB

• References

• 1 Italiano A, Mir O, Mathoulin-Pelissier S. et al. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2020; 21: 446-455
• 2 Smrke A, Anderson PM, Gulia A. et al. Future Directions in the Treatment of Osteosarcoma. Cells 2021; 10: 172
• 3 Bazavar M, Fazli J, Valizadeh A. et al. miR-192 enhances sensitivity of methotrexate drug to MG-63 osteosarcoma cancer cells. Pathol Res Pract 2020; 216: 153176
• 4 Siegel RL, Miller KD, Fuchs HE. et al. Cancer Statistics, 2021. CA Cancer J Clin 2021; 71: 7-33
• 5 Zheng D, Liu W, Xie W. et al. AHA1 upregulates IDH1 and metabolic activity to promote growth and metastasis and predicts prognosis in osteosarcoma. Signal Transduct Target Ther 2021; 6: 1-12
• 6 Asghari S, Valizadeh Dizajeykan A, Ahmadi M. et al. Evaluation of ovarian cancer risk in granulosa cells treated with steroid-depleted endometriosis serum: Role of NF-κB/RelA and AKT. J Cell Physiol 2019; 234: 12011-12018
• 7 Gong T, Su X, Xia Q. et al. Expression of NF-κB and PTEN in osteosarcoma and its clinical significance. Oncol Lett 2017; 14: 6744-6748
• 8 Ryan SL, Beard S, Barr MP. et al. Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC. Lung Cancer 2019; 135: 217-227
• 9 Hashemzaei M, Delarami Far A, Yari A. et al. Anticancer and apoptosis‑inducing effects of quercetin in vitro and in vivo. Oncol Rep 2017; 38: 819-828
• 10 Russo M, Spagnuolo C, Tedesco I. et al. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem Pharmacol 2012; 83: 6-15
• 11 Youn H, Jeong JC, Jeong YS. et al. Quercetin potentiates apoptosis by inhibiting nuclear factor-kappaB signaling in H460 lung cancer cells. Biol Pharm Bull 2013; 36: 944-951
• 12 Almeida LO, Abrahao AC, Rosselli-Murai LK. et al. NFκB mediates cisplatin resistance through histone modifications in head and neck squamous cell carcinoma (HNSCC). FEBS Open Bio 2014; 4: 96-104
• 13 Chen Z, Zeng Z, Zhu S. et al. Effects of different combined regimens of Cisplatin, metformin, and quercetin on nasopharyngeal carcinoma cells and subcutaneous xenografts. Sci Rep 2021; 11: 1-10
• 14 Chuang SE, Yeh PY, Lu YS. et al. Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells. Biochem Pharmacol 2002; 63: 1709-1716
• 15 Pan HC, Jiang Q, Yu Y. et al. Quercetin promotes cell apoptosis and inhibits the expression of MMP-9 and fibronectin via the AKT and ERK signalling pathways in human glioma cells. Neurochem Int 2015; 80: 60-71
• 16 Pozsgai E, Bellyei S, Cseh A. et al. Quercetin increases the efficacy of glioblastoma treatment compared to standard chemoradiotherapy by the suppression of PI-3-kinase-Akt pathway. Nutr Cancer 2013; 65: 1059-1066
• 17 Sun Y, Guan Z, Liang L. et al. NF-κB signaling plays irreplaceable roles in cisplatin-induced bladder cancer chemoresistance and tumor progression. Int J Oncol 2016; 48: 225-234
• 18 Lu J, Song G, Tang Q. et al. IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling. J Clin Invest 2015; 125: 1839-1856
• 19 Sun ZJ, Chen G, Hu X. et al. Activation of PI3K/Akt/IKK-alpha/NF-kappaB signaling pathway is required for the apoptosis-evasion in human salivary adenoid cystic carcinoma: its inhibition by quercetin. Apoptosis 2010; 15: 850-863
• 20 Fu J, Xu Y, Yang Y. et al. Aspirin suppresses chemoresistance and enhances antitumor activity of 5-Fu in 5-Fu-resistant colorectal cancer by abolishing 5-Fu-induced NF-κB activation. Sci Rep 2019; 9: 1-11
• 21 Li X, Guo S, Xiong XK. et al. Combination of quercetin and Cisplatin enhances apoptosis in OSCC cells by downregulating xIAP through the NF-κB pathway. J Cancer 2019; 10: 4509-4521
• 22 Zou H, Zheng YF, Ge W. et al. Synergistic Anti-tumour Effects of Quercetin and Oncolytic Adenovirus expressing TRAIL in Human Hepatocellular Carcinoma. Sci Rep 2018; 8: 1-8