High-throughput screening identifies artesunate as selective inhibitor of cancer stemness: Involvement of mitochondrial metabolism

Subedi, Amit; Futamura, Yushi; Nishi, Mayuko; Ryo, Akihide; Watanabe, Nobumoto; Osada, Hiroyuki

doi:10.1016/j.bbrc.2016.06.128

Cited by 29 publications

(22 citation statements)

References 34 publications

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“…However, the development of drugs that target crucial steps in the Wnt, Notch and Hh signaling pathways may not be effective or can be toxic, owing to the signaling crosstalk among these pathways. An alternative strategy may be to look in an unbiased and systematic manner at pharmacological entities that demonstrate preferential toxicity in CSCs over the total tumoral cell population (7,23). A previous study performed a screen for agents with epithelial CSC-specific toxicity and identified four compounds that consistently reduced the proportion of CSCs, including salinomycin, etoposide, abamectin and nigericin (7).…”

Section: Discussionmentioning

confidence: 99%

Ivermectin as an inhibitor of cancer stem‑like cells

et al. 2017

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The aim of the present study was to demonstrate that ivermectin preferentially inhibited cancer stem‑like cells (CSC) in breast cancer cells and downregulated the expression of 'stemness' genes. Computational searching of DrugBank, a database of approved drugs, was performed using the principles of two‑dimensional similarity searching; the chemical structure of salinomycin was used as a query. Growth inhibition of the breast cancer cell lin e MDA‑MB‑231 by ivermectin was investigated in the total cell population, in cell spheroids and in sorted cells that expressed cluster of differentiation (CD)44+/CD24‑. The effects of ivermectin treatment on the expression of pluripotency and self‑renewal transcription factors, such as homeobox protein nanog (nanog), octamer‑binding protein 4 (oct‑4) and SRY‑box 2 (sox‑2), were evaluated by reverse transcription‑quantitative polymerase chain reaction and western blotting. Ivermectin exhibited a similarity value of 0.78 in reference to salinomycin. Ivermectin demonstrated an inhibitory effect upon the growth of MDA‑MB‑231 cells in the range of 0.2‑8 µM. Ivermectin preferentially inhibits the viability of CSC‑enriched populations (CD44+/CD24‑ and cells growing in spheroids) compared with the total cell population. The opposite pattern was observed with paclitaxel treatment. Ivermectin exposure reduced the expression of nanog, oct‑4 and sox‑2 at the mRNA and protein levels. Ivermectin preferentially inhibited the CSC subpopulation in the MDA‑MB‑231 cells and downregulated the expression of genes involved in the maintenance of pluripotency and self‑renewal.

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Section: Discussionmentioning

confidence: 99%

Ivermectin as an inhibitor of cancer stem‑like cells

et al. 2017

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“…Notably, artemisinin was also solely identified in a high‐throughput screening study by Subedi et al. of approximately 6000 compounds as a selective inhibitor of cancer stemness . Using a model system of induced cancer stem like (iCSCL), the artemisinin analogue NPD2604 as well as artemisinin and artesunate were found to selectively and potently inhibit CSCs as determined by alkaline phosphatase assays and cell viability screenings between monolayer and 3D tumor sphere cultures.…”

Section: Molecular Targets and Signaling Pathways Implicated In The Amentioning

confidence: 99%

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action

Wong

Kalesh

et al. 2017

Medicinal Research Reviews

202

139

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“…[68] The natural product artesunate, which also is an anti-malarial drug, promotes mitochondrial dysfunction and kills induced cancer stem-like cells. [69] The FDA-approved antibacterial drug bedaquiline inhibits mitochondrial oxygen-consumption, as well as glycolysis, and causes oxidative stress in MCF-7 cells. Furthermore, it selectively targets CD44 high /CD24 low CSCs.…”

Section: Targeting the Metabolic State Of Cscs: Mitochondrial Metabolmentioning

confidence: 99%

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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High-throughput screening identifies artesunate as selective inhibitor of cancer stemness: Involvement of mitochondrial metabolism

Cited by 29 publications

References 34 publications

Ivermectin as an inhibitor of cancer stem‑like cells

Ivermectin as an inhibitor of cancer stem‑like cells

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action

Targeting Cancer Stem Cells with Small Molecules

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