Targeting Nrf2 May Reverse the Drug Resistance in Ovarian Cancer

Overview

Journal Cancer Cell Int

Publisher Biomed Central

Date 2021 Feb 18

PMID 33596893

Citations 21

Authors

Danjie Li

Xiaoling Hong

Feijie Zhao

Xinxin Ci

Songling Zhang

Affiliations

Soon will be listed here.

Abstract

Background: Acquired resistance to therapeutic drugs has become an important issue in treating ovarian cancer. Studies have shown that the prevalent chemotherapy resistance (cisplatin, paclitaxel etc.) for ovarian cancer occurs partly because of decreased production of reactive oxygen species within the mitochondria of ovarian cancer cells.

Main Body: Nuclear erythroid-related factor-2 (Nrf2) mainly controls the regulation of transcription of genes through the Keap1-Nrf2-ARE signaling pathway and protects cells by fighting oxidative stress and defending against harmful substances. This protective effect is reflected in the promotion of tumor cell growth and their resistance to chemotherapy drugs. Therefore, inhibition of the Nrf2 pathway may reverse drug resistance. In this review, we describe the functions of Nrf2 in drug resistance based on Nrf2-associated signaling pathways determined in previous studies.

Conclusions: Further studies on the relevant mechanisms of Nrf2 may help improve the outcomes of ovarian cancer therapy.

Citing Articles

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References

Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M . Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 2008; 68(5):1303-9. DOI: 10.1158/0008-5472.CAN-07-5003. View

Gauron C, Rampon C, Bouzaffour M, Ipendey E, Teillon J, Volovitch M . Sustained production of ROS triggers compensatory proliferation and is required for regeneration to proceed. Sci Rep. 2013; 3:2084. PMC: 3694286. DOI: 10.1038/srep02084. View

Jarboe E, Hirschowitz S, Geiersbach K, Wallander M, Tripp S, Layfield L . Juvenile granulosa cell tumors: immunoreactivity for CD99 and Fli-1 and EWSR1 translocation status: a study of 11 cases. Int J Gynecol Pathol. 2013; 33(1):11-5. DOI: 10.1097/PGP.0b013e31828309e6. View

Manandhar S, Lee S, Kwak M . Effect of stable inhibition of NRF2 on doxorubicin sensitivity in human ovarian carcinoma OV90 cells. Arch Pharm Res. 2010; 33(5):717-26. DOI: 10.1007/s12272-010-0511-z. View

Xia M, Yan X, Zhou L, Xu L, Zhang L, Yi H . p62 Suppressed VK3-induced Oxidative Damage Through Keap1/Nrf2 Pathway In Human Ovarian Cancer Cells. J Cancer. 2020; 11(6):1299-1307. PMC: 6995367. DOI: 10.7150/jca.34423. View

Liew P, Hsu C, Liu W, Lee Y, Lee Y, Chen C . Prognostic and predictive values of Nrf2, Keap1, p16 and E-cadherin expression in ovarian epithelial carcinoma. Int J Clin Exp Pathol. 2015; 8(5):5642-9. PMC: 4503147. View

Shin D, Kim E, Lee J, Roh J . Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med. 2018; 129:454-462. DOI: 10.1016/j.freeradbiomed.2018.10.426. View

Salatino A, Aversa I, Battaglia A, Sacco A, Di Vito A, Santamaria G . H-Ferritin Affects Cisplatin-Induced Cytotoxicity in Ovarian Cancer Cells through the Modulation of ROS. Oxid Med Cell Longev. 2019; 2019:3461251. PMC: 6875340. DOI: 10.1155/2019/3461251. View

Gao A, Ke Z, Wang J, Yang J, Chen S, Chen H . Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Carcinogenesis. 2013; 34(8):1806-14. DOI: 10.1093/carcin/bgt108. View

10.

Romero R, Sayin V, Davidson S, Bauer M, Singh S, LeBoeuf S . Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med. 2017; 23(11):1362-1368. PMC: 5677540. DOI: 10.1038/nm.4407. View

11.

Chen X, Yin T, Zhang B, Sun B, Chen J, Xiao T . Inhibitory effects of brusatol delivered using glycosaminoglycan‑placental chondroitin sulfate A‑modified nanoparticles on the proliferation, migration and invasion of cancer cells. Int J Mol Med. 2020; 46(2):817-827. PMC: 7307823. DOI: 10.3892/ijmm.2020.4627. View

12.

Zhong Y, Chen H, Tan B, Yu H, Huang X . Triptolide avoids cisplatin resistance and induces apoptosis via the reactive oxygen species/nuclear factor-κB pathway in SKOV3 platinum-resistant human ovarian cancer cells. Oncol Lett. 2013; 6(4):1084-1092. PMC: 3796418. DOI: 10.3892/ol.2013.1524. View

13.

Lord C, Ashworth A . PARP inhibitors: Synthetic lethality in the clinic. Science. 2017; 355(6330):1152-1158. PMC: 6175050. DOI: 10.1126/science.aam7344. View

14.

Chen J, Solomides C, Simpkins F, Simpkins H . The role of Nrf2 and ATF2 in resistance to platinum-based chemotherapy. Cancer Chemother Pharmacol. 2017; 79(2):369-380. DOI: 10.1007/s00280-016-3225-1. View

15.

Sajadimajd S, Khazaei M . Oxidative Stress and Cancer: The Role of Nrf2. Curr Cancer Drug Targets. 2017; 18(6):538-557. DOI: 10.2174/1568009617666171002144228. View

16.

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View

17.

Guelluy P, Fontaine-Aupart M, Grammenos A, Lecart S, Piette J, Hoebeke M . Optimizing photodynamic therapy by liposomal formulation of the photosensitizer pyropheophorbide-a methyl ester: in vitro and ex vivo comparative biophysical investigations in a colon carcinoma cell line. Photochem Photobiol Sci. 2010; 9(9):1252-60. DOI: 10.1039/c0pp00100g. View

18.

Meng Y, Chen C, Yung M, Sun W, Sun J, Li Z . DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR-Chk1 pathway in ovarian cancer. Cancer Lett. 2018; 428:104-116. PMC: 7474466. DOI: 10.1016/j.canlet.2018.04.029. View

19.

Tarumoto T, Nagai T, Ohmine K, Miyoshi T, Nakamura M, Kondo T . Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line. Exp Hematol. 2004; 32(4):375-81. DOI: 10.1016/j.exphem.2004.01.007. View

20.

Ozog D, Rkein A, Fabi S, Gold M, Goldman M, Lowe N . Photodynamic Therapy: A Clinical Consensus Guide. Dermatol Surg. 2016; 42(7):804-27. DOI: 10.1097/DSS.0000000000000800. View