Small-molecule blocks malignant astrocyte proliferation and induces neuronal gene expression

Abstract

In the central nervous system (CNS), neural stem cells (NSCs) differentiate into neurons, astrocytes, and oligodendrocytes - these cell lineages are considered unidirectional and irreversible under normal conditions. The introduction of a defined set of transcription factors has been shown to directly convert terminally differentiated cells into pluripotent stem cells, reinforcing the notion that preserving cellular identity is an active process. Indeed, recent studies highlight that tumor suppressor genes (TSGs) such as Ink4a/Arf and p53, control the barrier to efficient reprogramming, leaving open the question whether the same TSGs function to maintain the differentiated state. During malignancy or following brain injury, mature astrocytes have been reported to re-express neuronal genes and re-gain neurogenic potential to a certain degree, yet few studies have addressed the underlying mechanisms due to a limited number of cellular models or tools to probe this process. Here, we use a synthetic small-molecule (isoxazole) to demonstrate that highly malignant EGFRvIII-expressing Ink4a/Arf-/-; Pten-/- astrocytes down-regulated their astrocyte character, re-entered the cell cycle, and upregulated neuronal gene expression. As a collateral discovery, isoxazole small-molecules blocked tumor cell proliferation in vitro, a phenotype likely coupled to activation of neuronal gene expression. Similarly, histone deacetylase inhibitors induced neuronal gene expression and morphologic changes associated with the neuronal phenotype, suggesting the involvement of epigenetic-mediated gene activation. Our study assesses the contribution of specific genetic pathways underlying the de-differentiation potential of astrocytes and uncovers a novel pharmacological tool to explore astrocyte plasticity, which may bring insight to reprogramming and anti-tumor strategies.

Activity of 2-Aryl-2-(3-indolyl)acetohydroxamates against Drug-Resistant Cancer Cells

“…Although such redifferentiation processes are known, there are only a few small molecule agents reported to induce these epigenetic transformations. 33,34 The literature reports indicate that these redifferentiated cells possess significantly reduced tumorigenicity in vivo 33 and, thus, new chemical entities capable of triggering such phenotypic changes hold a promising but completely unexplored potential as anticancer agents.…”

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

“…107 It was also demonstrated that lsx suppressed the proliferation of malignant astrocytes. 108 To date, however, much advancement needs to be done in development of efficacious agonists and antagonists of the pH-sensing GPCRs coupled with a capacity to target specific tissue dysfunction in the midst of systemic drug administration to optimize therapeutic effects and minimize potential adverse effects.…”

Pharmacological Priming of Adipose-Derived Stem Cells Promotes Myocardial Repair

“…25 26 Transplantation of human peripheral blood mononuclear cells treated with the compounds we isolated in our Nkx2.5 screen improved cell engraftment and functional recovery in cryoinjured rat hearts 22. In addition, these molecules activated muscle-specific transcriptional programs in multipotent Notch-activated epicardium-derived cells (NECs),27 directed neuronal cell fate determination,24 28 induced myofibroblast differentiation,29 and increased insulin production in pancreatic β cells 30. We set out to test whether one of the most promising of these small molecules, a 3,5-disubstituted isoxazole (ISX1), could direct ADSCs into a cardiac lineage and foster myocardial repair.…”