Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol

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.

Keywords: BH3 mimetics; acute lymphoblastic leukemia; cannabidiol; drug repositioning; glucocorticoid-resistance; signaling pathways; tamoxifen; tigecycline.

Figure 1

Mechanisms of the GC action. Liposoluble GCs freely diffuse through the plasma membrane. Classically, they bind to specific intracellular GRs (α or γ isoforms) with the formation of GC-GR complexes, their posterior translocation to the nucleus and interaction with the GRE, which results in a transactivation or transrepression genomic activity (1). Alternative non-genomic mechanisms were also proposed, including the interaction with surface receptors (2) or the GCs retention in the plasma membrane and the interaction with integral proteins (3). Unable to bind GC, but transcriptionally active β isoform constitutively resides in the nucleus and can alternatively regulate many genes (4). GC-GR complexes translocate to mitochondria and interact with the OMM proteins, causing non-genomic effects (5). The lower panel shows the formation of alternative GR isoforms. See Chapter 1 for more details.

Figure 2

An overview of mechanisms of GC resistance in ALL and pharmacological strategies to overcome it. (Left) GC resistance in ALL is related to different genetic aberrations (see references in the text), which cause (1) upregulation of Notch, IL7R, Flt3, and MEK/ERK pathways, with a consequent upregulation of PI3K/Akt/mTOR and Glut1 and acceleration of cellular growth and metabolism; (2) downregulation of the proapoptotic proteins (BIM) and upregulation of the antiapoptotic proteins (Bcl-2, Bcl-XL, Mcl-1, and A1), with a consequent apoptosis inhibition; (3) overexpression of MDR proteins. A hypermethylation of BCL2L11 results in its inaccessibility to the transcriptional upregulation by a GR (left and upper right). The mTOR activation causes upregulation of glycolysis (middle right) and OXPHOS, and inhibition of autophagy. Upregulation of glycolysis can be opposed by the inhibition of hexokinase (HK), the first glycolytic enzyme. Ca²⁺ signaling is involved in the NFAT activation via the Ca²⁺-dependent dephosphorylation by calcineurin (CN). A sustained Ca²⁺ signal is achieved due to a repression of the recycling of ORAI (main Ca²⁺ influx component) and Kv1.3 (mediating K⁺ efflux, which supports Ca²⁺ influx) proteins via the PI3K/SGK1 pathway (lower right). The above mechanisms can be opposed by inhibitors of FLT3, IL7R, γ secretase, Akt1/2, P-gp, glycolysis, PI3K/AKT, SGK, and mTOR as well as by BH-3 mimetics and hypomethylating agents. A possible toxicity of PI3R/AKT/mTOR inhibitors as well as of glycolysis/ hexokinase (HK) inhibitors 3-bromopyruvate (3-BP), 2-deoxy-D-glucose (2-DG), 1-(2,4-dichlorobenzyl)-1H-indazol-3 carboxylic acid) (lonidamine, LND) needs to be considered. Some re-purposed drugs may improve antileukemic protocols: (1) TGC, which targets mitochondria and OXPHOS; (2) CBD, which targets mitochondria, causes the MTP-driven necrosis and inhibits P-gp; (3) TAM, which targets mitochondria, induces autophagy, inhibits P-gp and enhances the sensitivity to GCs; (4) anthelmintics, which inhibit GLUT1 and Hes1. For more details please consult the text.