PMID- 32194168 OWN - NLM STAT- MEDLINE DCOM- 20210805 LR - 20211111 IS - 1873-3913 (Electronic) IS - 0898-6568 (Print) IS - 0898-6568 (Linking) VI - 71 DP - 2020 Jul TI - The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice. PG - 109605 LID - S0898-6568(20)30082-6 [pii] LID - 10.1016/j.cellsig.2020.109605 [doi] AB - In a clinically-relevant model of 4 week, low-dose cisplatin-induced AKI, mice were injected subcutaneously with non small cell lung cancer (NSCLC) cells that harbor an activating Kirsten rat sarcoma viral oncogene homolog (KRAS)(G12V) mutation. Phospho extracellular signal-regulated kinase1/2 (pERK1/2) expression in kidney and tumors was decreased by the MEK1/2 inhibitors, U0126 and trametinib, that potently inhibit pERK1/2. U0126 resulted in a significant improvement in kidney function, acute tubular necrosis (ATN) and tubular cell apoptosis in mice with AKI. Genes that were significantly decreased by U0126 were heat shock protein 1, cyclin-dependent kinase 4 (CDK4) and stratifin (14-3-3sigma). U0126 resulted in a significant decrease in tumor weight and volume and significantly increased the chemotherapeutic effect of cisplatin. Trametinib, a MEK1/2 inhibitor that is FDA-approved for the treatment of cancer, did not result in functional protection against AKI or worse AKI, but dramatically decreased tumor growth more than cisplatin. Smaller tumors in cisplatin or MEK1/2 inhibitor-treated mice were not related to changes in microtubule-associated proteins 1A/1B light chain 3B (LC3-II), p62, cleaved caspase-3, granzyme B, or programmed death-ligand 1 (PD-L1). In summary, despite ERK inhibition by both U0126 and trametinib, only U0126 protected against AKI suggesting that the protection against AKI by U0126 was due to an off-target effect independent of ERK inhibition. The effect of U0126 to decrease AKI may be mediated by inhibition of heat shock protein 1, CDK4 or stratifin (14-3-3sigma). Trametinib was more effective than cisplatin in decreasing tumor growth, but unlike cisplatin, trametinib did not cause AKI. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Brown, Carolyn N AU - Brown CN AD - Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, CO, USA. FAU - Atwood, Daniel J AU - Atwood DJ AD - Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, CO, USA. FAU - Pokhrel, Deepak AU - Pokhrel D AD - Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, CO, USA. FAU - Ravichandran, Kameswaran AU - Ravichandran K AD - Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA. FAU - Holditch, Sara J AU - Holditch SJ AD - Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, CO, USA. FAU - Saxena, Sanskriti AU - Saxena S AD - Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, CO, USA. FAU - Miyazaki, Makoto AU - Miyazaki M AD - Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, CO, USA. FAU - Nemenoff, Raphael AU - Nemenoff R AD - Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, CO, USA. FAU - Weiser-Evans, Mary C M AU - Weiser-Evans MCM AD - Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, CO, USA. FAU - Ljubanovic, Danica Galesic AU - Ljubanovic DG AD - University of Zagreb School of Medicine, Dubrava University Hospital, Zagreb, Croatia. FAU - Joy, Melanie S AU - Joy MS AD - Skaggs School of Pharmacy and Pharmaceutical Sciences, Univ. of Colorado at Denver, Aurora, CO, USA. FAU - Edelstein, Charles L AU - Edelstein CL AD - Division of Renal Diseases and Hypertension, Univ. of Colorado at Denver, Aurora, CO, USA. Electronic address: Charles.edelstein@ucdenver.edu. LA - eng GR - I01 BX001737/BX/BLRD VA/United States GR - R01 HL133545/HL/NHLBI NIH HHS/United States GR - R01 HL117062/HL/NHLBI NIH HHS/United States GR - R01 DK096030/DK/NIDDK NIH HHS/United States GR - P30 NS048154/NS/NINDS NIH HHS/United States GR - R01 NS086839/NS/NINDS NIH HHS/United States GR - R01 HL132318/HL/NHLBI NIH HHS/United States GR - T32 GM007635/GM/NIGMS NIH HHS/United States GR - R01 GM107122/GM/NIGMS NIH HHS/United States GR - I01 BX003803/BX/BLRD VA/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20200316 PL - England TA - Cell Signal JT - Cellular signalling JID - 8904683 RN - 0 (Butadienes) RN - 0 (Lipocalin-2) RN - 0 (Neoplasm Proteins) RN - 0 (Nitriles) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridones) RN - 0 (Pyrimidinones) RN - 0 (U 0126) RN - 126469-30-5 (Lcn2 protein, mouse) RN - 33E86K87QN (trametinib) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Acute Kidney Injury/*drug therapy MH - Animals MH - Apoptosis/drug effects MH - Blood Urea Nitrogen MH - Butadienes/pharmacology MH - Cell Proliferation/drug effects MH - Cisplatin/pharmacology/*therapeutic use MH - Kidney/drug effects/injuries/pathology MH - Lipocalin-2/metabolism MH - Lung Neoplasms/pathology MH - MAP Kinase Signaling System/drug effects MH - Mice, Inbred C57BL MH - Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors/metabolism MH - Neoplasm Proteins/metabolism MH - Nitriles/pharmacology MH - Protein Kinase Inhibitors/*pharmacology MH - Pyridones/pharmacology MH - Pyrimidinones/pharmacology MH - Tumor Burden/drug effects PMC - PMC7592388 MID - NIHMS1637976 OTO - NOTNLM OT - AKI OT - Cancer OT - Cisplatin OT - ERK OT - Trametinib EDAT- 2020/03/21 06:00 MHDA- 2021/08/06 06:00 PMCR- 2020/10/28 CRDT- 2020/03/21 06:00 PHST- 2019/12/24 00:00 [received] PHST- 2020/03/13 00:00 [revised] PHST- 2020/03/15 00:00 [accepted] PHST- 2020/03/21 06:00 [pubmed] PHST- 2021/08/06 06:00 [medline] PHST- 2020/03/21 06:00 [entrez] PHST- 2020/10/28 00:00 [pmc-release] AID - S0898-6568(20)30082-6 [pii] AID - 10.1016/j.cellsig.2020.109605 [doi] PST - ppublish SO - Cell Signal. 2020 Jul;71:109605. doi: 10.1016/j.cellsig.2020.109605. Epub 2020 Mar 16.