U0126: Not Only a MAPK Kinase Inhibitor

Overview

Journal Front Pharmacol

Date 2022 Sep 12

PMID 36091807

Authors

Yijie You

Yunlian Niu

Jian Zhang

Sheng Huang

Peiyuan Ding

Fengbing Sun

Xuhui Wang

Affiliations

Soon will be listed here.

Abstract

U0126, as an inhibitor of the MAPK signaling pathway, is closely related to various biological processes, such as differentiation, cell growth, autophagy, apoptosis, and stress responses. It makes U0126 play an essential role in balancing cellular homeostasis. Although U0126 has been suggested to inhibit various cancers, its complete mechanisms have not been clarified in cancers. This review summarized the most recent and relevant research on the many applications of U0126 and described its role and mechanisms in different cancer cell types. Moreover, some acknowledged functions of U0126 researched in the laboratory were listed in our review. We discussed the probability of using U0126 to restain cancers or suppress the MAPK pathway as a novel way of cancer treatment.

Citing Articles

Targeting the ERK1/2 and p38 MAPK pathways attenuates Golgi tethering factor golgin-97 depletion-induced cancer progression in breast cancer.

Liu Y, Lin T, Chong K, Chen G, Kuo C, Lin Y Cell Commun Signal. 2025; 23(1):22.

PMID: 39800687 PMC: 11727508. DOI: 10.1186/s12964-024-02010-0.

Systems Biology Methods via Genome-Wide RNA Sequences to Investigate Pathogenic Mechanisms for Identifying Biomarkers and Constructing a DNN-Based Drug-Target Interaction Model to Predict Potential Molecular Drugs for Treating Atopic Dermatitis.

Chou S, Chuang Y, Chen B Int J Mol Sci. 2024; 25(19).

PMID: 39409019 PMC: 11477013. DOI: 10.3390/ijms251910691.

Applying a novel kinomics approach to study decidualization and the effects of antigestagens using a canine model†.

De Geyter I, Kowalewski M, Tavares Pereira M Biol Reprod. 2023; 110(3):583-598.

PMID: 38079525 PMC: 10941090. DOI: 10.1093/biolre/ioad170.

MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de‑methylases.

Zheng Z, Chen X, Zhang Y, Ren F, Ma Y Int J Oncol. 2023; 63(6).

PMID: 37921060 PMC: 10631768. DOI: 10.3892/ijo.2023.5588.

MicroRNA-Based Discovery of Biomarkers, Therapeutic Targets, and Repositioning Drugs for Breast Cancer.

Ye Q, Raese R, Luo D, Feng J, Xin W, Dong C Cells. 2023; 12(14).

PMID: 37508580 PMC: 10378316. DOI: 10.3390/cells12141917.

References

Eppstein A, Sandoval J, Klein P, Woodruff H, Grosfeld J, Hickey R . Differential sensitivity of chemoresistant neuroblastoma subtypes to MAPK-targeted treatment correlates with ERK, p53 expression, and signaling response to U0126. J Pediatr Surg. 2006; 41(1):252-9. DOI: 10.1016/j.jpedsurg.2005.10.047. View

Yip-Schneider M, Lin A, Marshall M . Pancreatic tumor cells with mutant K-ras suppress ERK activity by MEK-dependent induction of MAP kinase phosphatase-2. Biochem Biophys Res Commun. 2001; 280(4):992-7. DOI: 10.1006/bbrc.2001.4243. View

Rejiba S, Wack S, Aprahamian M, Hajri A . K-ras oncogene silencing strategy reduces tumor growth and enhances gemcitabine chemotherapy efficacy for pancreatic cancer treatment. Cancer Sci. 2007; 98(7):1128-36. PMC: 11159785. DOI: 10.1111/j.1349-7006.2007.00506.x. View

Ma X, Wang Q, Liu Y, Chen Y, Zhang L, Jiang M . Inhibition of tumor growth by U0126 is associated with induction of interferon-γ production. Int J Cancer. 2014; 136(4):771-83. DOI: 10.1002/ijc.29038. View

Bachireddy P, Bendapudi P, Felsher D . Getting at MYC through RAS. Clin Cancer Res. 2005; 11(12):4278-81. DOI: 10.1158/1078-0432.CCR-05-0534. View

Farrokhnia N, Ericsson A, Terent A, Lennmyr F . MEK-inhibitor U0126 in hyperglycaemic focal ischaemic brain injury in the rat. Eur J Clin Invest. 2008; 38(9):679-85. DOI: 10.1111/j.1365-2362.2008.01990.x. View

Yacoub A, Han S, Caron R, Gilfor D, Mooberry S, Grant S . Sequence dependent exposure of mammary carcinoma cells to Taxotere and the MEK1/2 inhibitor U0126 causes enhanced cell killing in vitro. Cancer Biol Ther. 2003; 2(6):670-6. View

Zhao L, Huang C, Li Z, Liu L, Ni L, Song T . STAT1/2 is involved in the inhibition of cell growth induced by U0126 in HeLa cells. Cell Mol Biol (Noisy-le-grand). 2009; 55 Suppl:OL1168-74. View

de Tomaso Portaz A, Caimi G, Sanchez M, Chiappini F, Randi A, Kleiman de Pisarev D . Hexachlorobenzene induces cell proliferation, and aryl hydrocarbon receptor expression (AhR) in rat liver preneoplastic foci, and in the human hepatoma cell line HepG2. AhR is a mediator of ERK1/2 signaling, and cell cycle regulation in HCB-treated.... Toxicology. 2015; 336:36-47. DOI: 10.1016/j.tox.2015.07.013. View

10.

Gao J, Niwa K, Takemura M, Sun W, Onogi K, Wu Y . Significant anti-proliferation of human endometrial cancer cells by combined treatment with a selective COX-2 inhibitor NS398 and specific MEK inhibitor U0126. Int J Oncol. 2005; 26(3):737-44. View

11.

Cossa G, Gatti L, Cassinelli G, Lanzi C, Zaffaroni N, Perego P . Modulation of sensitivity to antitumor agents by targeting the MAPK survival pathway. Curr Pharm Des. 2012; 19(5):883-94. View

12.

Jain M, Arvanitis C, Chu K, Dewey W, Leonhardt E, Trinh M . Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science. 2002; 297(5578):102-4. DOI: 10.1126/science.1071489. View

13.

Aguirre Ghiso J, Alonso D, Farias E, Gomez D, de Kier Joffe E . Deregulation of the signaling pathways controlling urokinase production. Its relationship with the invasive phenotype. Eur J Biochem. 1999; 263(2):295-304. DOI: 10.1046/j.1432-1327.1999.00507.x. View

14.

Mattingly R, Milstein M, Mirkin B . Down-regulation of growth factor-stimulated MAP kinase signaling in cytotoxic drug-resistant human neuroblastoma cells. Cell Signal. 2001; 13(7):499-505. DOI: 10.1016/s0898-6568(01)00173-5. View

15.

Giroux S, Tremblay M, Bernard D, Aubry S, Larouche L, Rousseau S . Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr Biol. 1999; 9(7):369-72. DOI: 10.1016/s0960-9822(99)80164-x. View

16.

Christensen S, Johansson S, Radziwon-Balicka A, Warfvinge K, Haanes K, Edvinsson L . MEK1/2 inhibitor U0126, but not nimodipine, reduces upregulation of cerebrovascular contractile receptors after subarachnoid haemorrhage in rats. PLoS One. 2019; 14(4):e0215398. PMC: 6461292. DOI: 10.1371/journal.pone.0215398. View

17.

McCubrey J, Steelman L, Chappell W, Abrams S, Wong E, Chang F . Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2006; 1773(8):1263-84. PMC: 2696318. DOI: 10.1016/j.bbamcr.2006.10.001. View

18.

Levin B . Gallbladder carcinoma. Ann Oncol. 1999; 10 Suppl 4:129-30. View

19.

Mizuguchi M, Kudo S, Fukahori T, Matsuo Y, Miyazaki K, Tokunaga O . Endoscopic ultrasonography for demonstrating loss of multiple-layer pattern of the thickened gallbladder wall in the preoperative diagnosis of gallbladder cancer. Eur Radiol. 1997; 7(8):1323-7. DOI: 10.1007/s003300050296. View

20.

Schoenborn J, Wilson C . Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol. 2007; 96:41-101. DOI: 10.1016/S0065-2776(07)96002-2. View