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Olivas-Aguirre M, Torres-López L, Pottosin I, et al. Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol. Front Oncol. 2021;11:617937doi: 10.3389/fonc.2021.617937.
Olivas-Aguirre, M., Torres-López, L., Pottosin, I., & Dobrovinskaya, O. (2021). Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol. Frontiers in oncology, 11617937. https://doi.org/10.3389/fonc.2021.617937
Olivas-Aguirre, Miguel, et al. "Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol." Frontiers in oncology vol. 11 (2021): 617937. doi: https://doi.org/10.3389/fonc.2021.617937
Olivas-Aguirre M, Torres-López L, Pottosin I, Dobrovinskaya O. Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol. Front Oncol. 2021 Mar 11;11:617937. doi: 10.3389/fonc.2021.617937. eCollection 2021. PMID: 33777761; PMCID: PMC7991804.
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Front Oncol. 2021 Mar 11;11:617937. doi: 10.3389/fonc.2021.617937. eCollection 2021.

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

Frontiers in oncology

Miguel Olivas-Aguirre, Liliana Torres-López, Igor Pottosin, Oxana Dobrovinskaya

Affiliations

  1. Laboratory of Immunobiology and Ionic Transport Regulation, University Center for Biomedical Research, University of Colima, Colima, Mexico.

PMID: 33777761 PMCID: PMC7991804 DOI: 10.3389/fonc.2021.617937

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.

Copyright © 2021 Olivas-Aguirre, Torres-López, Pottosin and Dobrovinskaya.

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

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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