Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds

Würth, Roberto; Thellung, Stefano; Bajetto, Adriana; Mazzanti, Michele; Florio, Tullio; Barbieri, Federica

doi:10.1016/j.drudis.2015.09.017

Cited by 125 publications

(90 citation statements)

References 123 publications

(127 reference statements)

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“…GBM CSCs are resistant to conventional chemo-radiotherapy due to high activity of DNA repairing enzyme and drug efflux pumps, and their persistence after cytotoxic therapy is believed to determine tumor recurrence [42, 43]. In virtue of these proprieties, GBM CSCs represent the focus for novel targeted therapies [44, 45]; moreover, the identification of specific signaling pathways responsible for the retention of stemness, might have a significant translational relevance, contributing to the eradication of this cell subpopulation.…”

Section: Introductionmentioning

confidence: 99%

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

et al. 2016

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Prion protein (PrPC) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrPC is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrPC regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrPC in GBM cell pathogenicity focusing on tumor-initiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrPC expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrPC expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrPC down-regulated cells. Moreover, PrPC down-regulation caused loss of expression of the stemness and self-renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrPC controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype.

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Section: Introductionmentioning

confidence: 99%

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

et al. 2016

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“…Anticancer activities of several anthelminthics attracted considerable interest, especially their capacity to target signal transduction pathways of CSCs/TICs of several tumor types. Aside of the inhibition of signal transduction, on-target repositioning assumes that the targets recognized in nematods, such as mitochondrial respiration and microtubules, are hit in cancer cells [70,89,90]. However, the multitude of effects observed in response to the anthelminthics cannot be explained by specific and defined intracellular targets.…”

Section: Resultsmentioning

confidence: 99%

Repurposing of Anthelminthics as Anticancer Drugs

Hamilton¹,

Rath²

2018

Oncomedicine

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“…In recent years there has been growing interest in drug repurposing or repositioning, a process which seeks to identify new pharmacologic properties (e.g., anti-tumorigenic) of existing medications for use as primary or adjuvant treatments for other conditions (38, 39). These drugs are already well-studied in terms of tolerability and side effects, often inexpensive, and amenable to retrospective and associative studies as many patients are already taking them for other indications.…”

Section: Metformin Repurposing and Epidemiologic Data From Endometriamentioning

confidence: 99%

Metformin as a Therapeutic Target in Endometrial Cancers

et al. 2018

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Endometrial cancer is the most common gynecologic malignancy in developed countries. Its increasing incidence is thought to be related in part to the rise of metabolic syndrome, which has been shown to be a risk factor for the development of hyperestrogenic and hyperinsulinemic states. This has consequently lead to an increase in other hormone-responsive cancers as well e.g., breast and ovarian cancer. The correlation between obesity, hyperglycemia, and endometrial cancer has highlighted the important role of metabolism in cancer establishment and persistence. Tumor-mediated reprogramming of the microenvironment and macroenvironment can range from induction of cytokines and growth factors to stimulation of surrounding stromal cells to produce energy-rich catabolites, fueling the growth, and survival of cancer cells. Such mechanisms raise the prospect of the metabolic microenvironment itself as a viable target for treatment of malignancies. Metformin is a biguanide drug that is a first-line treatment for type 2 diabetes that has beneficial effects on various markers of the metabolic syndrome. Many studies suggest that metformin shows potential as an adjuvant treatment for uterine and other cancers. Here, we review the evidence for metformin as a treatment for cancers of the endometrium. We discuss the available clinical data and the molecular mechanisms by which it may exert its effects, with a focus on how it may alter the tumor microenvironment. The pleiotropic effects of metformin on cellular energy production and usage as well as intercellular and hormone-based interactions make it a promising candidate for reprogramming of the cancer ecosystem. This, along with other treatments aimed at targeting tumor metabolic pathways, may lead to novel treatment strategies for endometrial cancer.

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Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds

Cited by 125 publications

References 123 publications

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells

Repurposing of Anthelminthics as Anticancer Drugs

Metformin as a Therapeutic Target in Endometrial Cancers

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