Abstract
Glucocorticoids (GCs) are a central component of multi-drug treatment protocols against T and B acute lymphoblastic leukemia (ALL), which are used intensively during the remission induction to rapidly eliminate the leukemic blasts. The primary response to GCs predicts the overall response to treatment and clinical outcome. In this review, we have critically analyzed the available data on the effects of GCs on sensitive and resistant leukemic cells, in order to reveal the mechanisms of GC resistance and how these mechanisms may determine a poor outcome in ALL. Apart of the GC resistance, associated with a decreased expression of receptors to GCs, there are several additional mechanisms, triggered by alterations of different signaling pathways, which cause the metabolic reprogramming, with an enhanced level of glycolysis and oxidative phosphorylation, apoptosis resistance, and multidrug resistance. Due to all this, the GC-resistant ALL show a poor sensitivity to conventional chemotherapeutic protocols. We propose pharmacological strategies that can trigger alternative intracellular pathways to revert or overcome GC resistance. Specifically, we focused our search on drugs, which are already approved for treatment of other diseases and demonstrated anti-ALL effects in experimental pre-clinical models. Among them are some “truly” re-purposed drugs, which have different targets in ALL as compared to other diseases: cannabidiol, which targets mitochondria and causes the mitochondrial permeability transition-driven necrosis, tamoxifen, which induces autophagy and cell death, and reverts GC resistance through the mechanisms independent of nuclear estrogen receptors (“off-target effects”), antibiotic tigecycline, which inhibits mitochondrial respiration, causing energy crisis and cell death, and some anthelmintic drugs. Additionally, we have listed compounds that show a classical mechanism of action in ALL but are not used still in treatment protocols: the BH3 mimetic venetoclax, which inhibits the anti-apoptotic protein Bcl-2, the hypomethylating agent 5-azacytidine, which restores the expression of the pro-apoptotic BIM, and compounds targeting the PI3K-Akt-mTOR axis. Accordingly, these drugs may be considered for the inclusion into chemotherapeutic protocols for GC-resistant ALL treatments.
Highlights
Acute lymphoblastic leukemia (ALL) represents a heterogeneous group of hematological malignancies, originated from T (T-acute lymphoblastic leukemia (ALL)) or B (B-ALL) cells progenitors
Mechanisms responsible for GC resistance can be divided into the two large groups: those associated with a reduced expression of functional Glucocorticoid Receptors (GR) and those that are not
One of the strategies already used in the therapy against the Acute Myeloid Leukemia (AML) is a simultaneous application of BH3 mimetics to inhibit the pro-survival Bcl-2 members and Hypomethylating Agents (HMA) to enhance the BIM expression
Summary
Acute lymphoblastic leukemia (ALL) represents a heterogeneous group of hematological malignancies, originated from T (T-ALL) or B (B-ALL) cells progenitors. BIM protein, which precludes the anti-apoptotic activity of Bcl-2, Bcl-XL, and Mcl-1, was demonstrated to trigger apoptosis in GC-sensitive cells [48, 49] It is well-known that endogenous GCs are essential for regulation of energy metabolism in different human tissues under physiological and stress conditions [50]. GLUT1 gene is not a direct target for GRs. The mechanism, underlying the inhibition of glycolysis, seems to be related to MYC, which is known to induce the expression of glucose transporters and some glycolytic enzymes in leukemic cells, and it is downregulated rapidly during GC treatments [44]. Diagnosis Relapse Relapse ND ND Diagnosis t [17, 19](q22;p13) TCF3-HLF (E2A-HLF) fusion gene Relapse TBL1XR1 delitions
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