The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice |
| |
| Affiliation: | 1. Division of Cardiology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy;2. Department of Oncology, Radiation Oncology, University of Turin, Torino, Italy;3. Department of Surgical Sciences, University of Turin, Torino, Italy;4. Nephrology Department, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy;1. Division of Nephrology, University Health Network, University of Toronto, Toronto, ON, Canada;2. Division of Pathology, University Health Network, University of Toronto, Toronto, ON, Canada;3. Division of Medical Oncology and Hematology, University Health Network, University of Toronto, Toronto, ON, Canada;1. The Dartmouth Institute for Health Policy and Clinical Practice, Audrey and Theodor Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire;2. Department of Medicine, Audrey and Theodor Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire;3. Department of Community and Family Medicine, Audrey and Theodor Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire;4. Department of Cardiology, Virgen Macarena University Hospital, Seville, Spain;5. Hospital São Lucas, PUCRS, Porto Alegre, Rio Grande do Sul, Brazil;6. Department of Cardiology, Odense University Hospital, Odense, Denmark;7. Department of Cardiology, University Hospital Basel, Petersgraben, Switzerland;8. Division of Cardiology, Misericordia e Dolce Hospital, Prato, Italy;9. Fletcher Allen Health Care, University of Vermont School of Medicine, Burlington, Vermont |
| |
| Abstract: | 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 (14–3-3σ). 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 (14–3-3σ). Trametinib was more effective than cisplatin in decreasing tumor growth, but unlike cisplatin, trametinib did not cause AKI. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
