High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells

Gerby, Bastien; Veiga, Diogo F.T.; Krošl, Jana; Nourreddine, Sami; Ouellette, Julianne; Haman, André; Lavoie, Geneviève; Fares, Iman; Tremblay, Mathieu; Litalien, Véronique; Ottoni, Elizabeth; Kosic, Milena; Geoffrion, Dominique; Ryan, Joël; Maddox, Paul S.; Chagraoui, Jalila; Marinier, Anne; Sauvageau, Guy; Kwok, Benjamin H.; Roux, Philippe P.; Hoang, Trang

doi:10.1172/jci86489

Cited by 33 publications

(32 citation statements)

References 78 publications

(128 reference statements)

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“…Interestingly, another highthroughput screen for compounds targeting LSCs independently identified 2-methoxyestradiol. [32] This study implicated the Notch signaling pathway and the down-regulation of MYC was reported. …”

Section: Unbiased Screening Approaches -Case-studiesmentioning

confidence: 82%

Targeting Cancer Stem Cells with Small Molecules

Müller

Cañeque

Acevedo

et al. 2017

Israel Journal of Chemistry

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Cancers arise as a result of physiological imbalances and subsequent uncontrolled cell division. Cancer initiation requires a set of biochemical alterations, including some occurring at the genetic and epigenetic levels. Thus, tumors are heterogeneous in nature making it challenging to selectively target different cancer cells by means of small molecule intervention. The paradigm of cancer stem cells (CSCs) describes subpopulations of cells with high selfrenewal and tumor-seeding capacity. These cells, typically refractory to conventional therapies, can give rise to relapse after treatment. Combinatorial strategies, including drugs that selectively target this population of cells, have emerged in recent years. Here, we review how discovery-basedunbiased -screening approaches [1] have helped identify small molecules that specifically target CSCs. We also highlight biological pathways characteristic of CSCs that can potentially be selectively targeted in a hypothesis-driven manner by small molecules. We describe molecules that effectively target CSCs and emphasize what is known about their biological modes of action. The diversity and complexity of biochemical processes that CSCs may be addicted to, raises the question of how selective targeting of these pathways can be achieved. This challenge may be addressed by the continuing production of structurally complex and diverse small molecules using target and diversity-oriented synthesis approaches.[2]

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Section: Unbiased Screening Approaches -Case-studiesmentioning

confidence: 82%

Targeting Cancer Stem Cells with Small Molecules

Müller

Cañeque

Acevedo

et al. 2017

Israel Journal of Chemistry

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“…Given intrinsically higher ROS levels and exhaustion of the antioxidant system, such a treatment could be selective for leukemic cells vs. noncancer ones. Both approaches, either the induction of ROS by cytabarine, arsenic trioxide and adaphostin, or glutathione depletion and SOD suppression by phenethyl isothiocyanate or 2‐methoxyestradiol, respectively, were able to induce cell death in diverse B‐ and T‐ALL cell lines or sensitize them to chemotherapy.…”

Section: Targeting Mitochondria In Therapy Of T‐allmentioning

confidence: 99%

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

Olivas-Aguirre

Pottosin

Dobrovinskaya

2019

Journal of Leukocyte Biology

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Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of hematologic malignancies, arising from diverse genetic alterations in the early lymphocyte development. T‐cell subtype of ALL (T‐ALL) accounts for about 15% and 25% of ALL in children and adults, respectively. Being less frequent among ALL subtypes, T‐ALL represents a high‐risk factor for poor prognosis due to its aggressiveness and resistance to common antileukemic drugs. Mitochondria were widely explored recently as a target for anticancer treatment because they are involved in a metabolic reprogramming of a cancer cell and play key roles in reactive oxygen species generation, Ca2+ signaling, and cell death induction. Accordingly, a new class of anticancer compounds named mitocans has been developed, which target mitochondria at distinct crucial points to promote their dysfunction and subsequent cell death. The present review analyses the role of mitochondria in malignant reprogramming and emerging therapeutic strategies targeting mitochondria as an “Achilles’ heel” in T‐ALL, with an emphasis on BH3 mimetics, sequestering pro‐survival BCL proteins and voltage‐dependent anion channel (VDAC)1‐directed drugs, which promote the suppression of aerobic glycolysis, VDAC1 closure, mitochondrial Ca2+ overload, stoppage of the oxidative phosphorylation, oxidative stress, and release of proapoptotic factors.

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“…We sought to determine whether proscillaridin could target leukemic stem cells since MYC is driving their proliferation (LSCs) (37)(38)(39). To explore this possibility, we used two LSC models, a mouse model of T-ALL and a LSC model of human acute myeloid leukemia (AML) (37,40,41). First, pre-LSCs T-ALL cells were isolated from a transgenic mouse model that closely reproduces human T-ALL (42).…”

Section: Proscillaridin Efficiently Targets Myc-driven Leukemic Stem mentioning

confidence: 99%

“…First, pre-LSCs T-ALL cells were isolated from a transgenic mouse model that closely reproduces human T-ALL (42). We previously showed that these pre-LSCs are driven by the SCL/TAL1 and LMO1 oncogenes, which depend on NOTCH1-MYC pathways, and are resistant to chemotherapeutic drugs used against leukemia (doxorubicin, camptothecin and dexamethasone) (5,37). Proscillaridin (3-10 nM) significantly decreased pre-LSC T-ALL viability by 70% after 4 days of treatment (Figure 2a).…”

Section: Proscillaridin Efficiently Targets Myc-driven Leukemic Stem mentioning

confidence: 99%

Targeting MYC Overexpressing Leukemia with Cardiac Glycoside Proscillaridin Through Downregulation of Histone Acetyltransferases

Costa

Armaos

McInnes

et al. 2018

Preprint

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Targeting MYC oncogene remains a major therapeutic goal in cancer chemotherapy. Here, we demonstrate that proscillaridin, a cardiac glycoside approved for heart failure treatment exhibit anticancer selectivity towards high MYC expressing leukemic cell lines and leukemia stem cells. At a clinically relevant concentration, proscillaridin induced a rapid downregulation of MYC protein level, due to a significant decrease in MYC protein half-life. Proscillaridin treatment induced a downregulation of gene sets involved in MYC pathway, and a concomitant upregulation of genes involved in hematopoietic differentiation. Proscillaridin induced a significant loss of lysine acetylation in histone H3 (K9, K14, K18 and K27) and in non-histone proteins such as MYC, MYC target proteins, and a series of histone acetylation regulators. Loss of lysine acetylation correlated with a rapid downregulation of histone acetyltransferase protein levels, involved in histone and MYC acetylation (CBP, P300, GCN5, TIP60, and MOZ), preferentially in MYC overexpressing leukemia as compared to other cancer cells.These results support the repurposing of proscillaridin in MYC overexpressing leukemia and propose a novel strategy to target MYC in cancer.

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High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells

Cited by 33 publications

References 78 publications

Targeting Cancer Stem Cells with Small Molecules

Targeting Cancer Stem Cells with Small Molecules

Mitochondria as emerging targets for therapies against T cell acute lymphoblastic leukemia

Targeting MYC Overexpressing Leukemia with Cardiac Glycoside Proscillaridin Through Downregulation of Histone Acetyltransferases

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