Targetting a Pro-Apoptotic Molecule BIM by Dexamethasone and MEK Inhibitors Synergistically Induces Apoptosis in Acute Lymphoblastic Leukemia Cells.
Authors: Harada Hisashi , Rambal Anila A , Panaguiton Zarah Liz G 
Published: April 2020

Abstract
Glucocorticoids (GC) are common components in many chemotherapeutic protocols for lymphoid/myeloid malignancies, including ALL, multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin’s lymphoma. GC-induced apoptosis is essentially divided three stages:
an initiation stage, which involves glucocorticoid receptor (GR) activation and GR-mediated gene regulation; a decision stage, which engages pro- and anti-apoptotic BCL-2 family proteins at the mitochondrial level; and execution stage, which implicates caspases and endonucleases activation.
Although the effects of GC on lymphocytes have been scrutinized for many years, the molecular mechanisms of sensitivity and resistance are still elusive. Since GC-resistant leukemia and myeloma are often associated with GR defects, bypassing the receptor by targeting downstream molecules may develop new therapeutic strategies. Numerous novel drug combinations are currently being tested to prevent resistance and improve GC efficacy in the therapy of lymphoid malignancies. However, it is still not entirely clear how the signaling pathways and their downstream target molecules, including the BCL-2 family members, participate in GC-induced cell death. We and others have shown that BIM (BCL-2 interacting mediator of cell death), a BH3-only pro-apoptotic BCL-2 family protein, is up-regulated by dexamethasone (Dex) treatment in acute lymphoblastic leukemia (ALL) cells and plays an essential role in Dex-induced apoptosis. Furthermore, BIM is inactivated by extracellular signal-regulated kinase (ERK)-mediated phosphorylation. We therefore hypothesized co-treatment with Dex and MEK/ERK inhibitors would promote apoptosis in ALL cells through BIM upregulation and activation. We show here that MEK inhibitors (PD184352 and PD98059) synergistically enhance Dex lethality in both T-ALL and B-ALL cells. Co-treatment with Dex and PD184352 results in BIM accumulation, pro-apoptotic BAX/BAK activation, and cytochrome c release from mitochondria. Down-regulation of BIM by short-hairpin RNA in CCRF-CEM (T-ALL) and RS4;11 (B-ALL) cells almost completely suppressed BAX/BAK activation, cytochrome c release, and cell death by Dex/PD184352 co-treatment. BIM accumulated by this co-treatment sequesters anti-apoptotic BCL-XL/MCL-1, resulting in the release of BAK from these anti-apoptotic molecules. The main concept is that we have a novel and potentially effective way to increase GC activity against ALL cells, which may reflect the fact that
GCs up-regulate BIM; and pharmacologic MEK inhibitors further potentiate BIM activation by blocking BIM phosphorylation and degradation.
Our study provides a rational foundation for future attempts to improve the effect of glucocorticoids with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematological malignancies. BIM also plays an important role in cell death induced by other chemotherapeutic drugs such as STI571 (imatinib mesylate) and histone deacetylase inhibitors. Thus, targeting BIM by drugs combination could be effective on other tumors.