The Pharmacological Inhibition of ERK5 Enhances Apoptosis in Acute Myeloid Leukemia Cells

Abstract
Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by poor prognosis and a high degree of resistance to conventional chemotherapy. Emerging evidence highlights the role of extracellular signal-regulated kinase 5 (ERK5) in mediating chemoresistance and regulating key processes such as cell survival and apoptosis. This study aimed to evaluate the impact of the selective ERK5 inhibitor, XMD8-92, on AML cell proliferation and apoptosis. Our results demonstrated that XMD8-92 effectively suppressed G-CSF-induced ERK5 activation and reduced the expression of oncogenic proteins c-Myc and Cyclin D1. Inhibition of ERK5 phosphorylation by XMD8-92 led to a marked decrease in cell proliferation and a significant increase in apoptotic activity in AML cell lines Kasumi-1 and HL-60.

Moreover, treatment with XMD8-92 resulted in the upregulation of pro-apoptotic markers, including Bax and cleaved caspase-3, while concurrently downregulating the anti-apoptotic protein Bcl-2. These molecular alterations indicate that ERK5 plays a critical role in sustaining AML cell survival, and its inhibition shifts the cellular balance toward programmed cell death. Importantly, XMD8-92 exhibited low cytotoxicity in normal hematopoietic cells, suggesting a favorable therapeutic index. Collectively, these findings underscore the potential of ERK5 inhibition as a promising therapeutic strategy, both as a standalone treatment and in combination with standard chemotherapy, to enhance treatment outcomes and overcome resistance in AML. Future investigations will focus on validating these effects in in vivo models and identifying biomarkers that may predict responsiveness to ERK5-targeted therapies.