A Molecular Screening Approach to Identify and Characterize Inhibitors of Glioblastoma Stem Cells

Visnyei, Koppany; Onodera, Hideyuki; Damoiseaux, Robert; Saigusa, Kuniyasu; Petrosyan, Syuzanna; Vries, David De; Ferrari, Denise; Saxe, Jonathan P.; Panosyan, Eduard H.; Masterman‐Smith, Michael; Mottahedeh, Jack; Bradley, Kenneth A.; Huang, Jing; Sabatti, Chiara; Nakano, ﻿Ichiro; Kornblum, Harley I.

doi:10.1158/1535-7163.mct-11-0268

Cited by 80 publications

(66 citation statements)

References 44 publications

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“…Of the 1,937 compounds we screened, we settled on DI for initial testing owing to its abilities to inhibit growth, inhibit self-renewal, and encourage differentiation of cells it fails to kill. We note that recent reports by other groups confirm many of the other potential drugs we identified, such as emetine (60). Brain-penetrating, DI-loaded PLGA nanoparticles inhibit growth of intracranial tumors in an animal model that closely reflects many aspects of human GBM.…”

Section: Discussionsupporting

confidence: 81%

“…Initial hits were subsequently evaluated for inhibition of GS5 sphere formation, a measure of BCSC selfrenewal. Thirty-two candidate compounds were identified ( Table Standard without S2), some of which were later confirmed in an independent highthroughput screen in BCSCs (60). The BCSC growth-inhibiting activity of many compounds was confirmed using AlamarBlue.…”

Section: Resultsmentioning

confidence: 91%

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Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma

Zhou

Patel

Sirianni³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

236

229

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Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: ( i ) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and ( ii ) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 91%

Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma

Zhou

Patel

Sirianni³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

236

229

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“…N-acyl-dopamines, including PDA, ODA, and NADA, have also been to have anti-inflammatory effects (48). Besides, the antitumor activity of cannabinoids has been documented (29,49). Here, we show for the first time that NADA has an anti-RAS transformation activity and that this activity relies on the core structure combining the dopamine and arachidonic acid moieties and is independent of its function through dopamine, cannabinoid, and vanilloid receptors (Fig.…”

Section: Discussionmentioning

confidence: 68%

“…Interestingly, all of the three compounds belong to a family of lipid-soluble dopamine compounds, N-acyl-dopamines, condensated of long-chain fatty acids and dopamine at its NH 2 -terminus (28). They are all naturally produced molecules sharing not only common structures but also similar biological characteristics, including function as neurotransmitters and as ligands of cannabinoid and vanilloid receptors (29,30).…”

Section: Lead Compound Identificationmentioning

confidence: 99%

N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation

Huang

Zhang

et al. 2017

Molecular Cancer Therapeutics

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RAS oncogenic mutations are common in human cancers, but RAS proteins have been difficult to target. We sought to identify pharmacological agents to block RAS oncogenic signaling by a distinct mechanism. Because the biological activity of RAS proteins relies upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we screened a bioactive lipid library using a RAS-specific cell viability assay. We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N-arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors. Further analyses show that NADA is more active in inhibiting the NRAS transformation and signaling than that of KRAS4B. Mechanistically, NADA blocks the plasma membrane translocation of NRAS, but not that of KRAS4B. In addition, NADA inhibits plasma membrane translocation and neoplastic transformation of oncogenic KRAS4A. Interestingly, NADA also redistributes the cytoplasmic NRAS to the Golgi apparatus in a palmitoylation-dependent manner. The results indicate that NADA inhibits NRAS and KRAS4A plasma membrane translocation by targeting a novel molecular process. The new findings would help to develop novel targeted therapies for a broad range of human cancers.

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“…However, in the presence of both N2 and F12, the sphere forming efficiency continues to increase over the passages, indicating that the CSCs are expanding with each passage. Our data indicates that optimized spheroid culture conditions can be potentially used to propagate and expand CSC from colon cancer cell lines and provide a practical method for development of relatively high-throughput drug screening assays for CSC-targeted therapy [44].…”

Section: Discussionmentioning

confidence: 89%

Enrichment and Selective Targeting of Cancer Stem Cells in Colorectal Cancer Cell Lines

Wang¹,

Kanojia²,

Lo³

et al. 2013

Human Genet Embryol

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Cancer stem cells (CSCs) are the subpopulation of cells within a tumor proposed to be responsible for tumor initiation, relapses, and resistance to chemotherapeutic drugs. Here we optimized sphere culture conditions to isolate and enrich CSCs from colorectal cancer cell line IMCE-Ras. Spheroid cells that developed in culture expressed high levels of putative stem cell markers, and showed stronger anchorage-independent growth abilities and resistance to conventional chemotherapeutic drugs compared with the initial monolayer adherent cells. Xenograft transplantation assays further demonstrated that IMCE-Ras spheroid cells are highly enriched in CSCs. To develop CSC-targeted therapy, we found that the relative percentage of CSC in IMCE-Ras cells was significantly decreased after a short duration exposure to DNA Methylation inhibitor 5-aza-2'-deoxycytidine (5-Aza-dC), indicating that DNA Methylation may be critical for self-renewal and maintenance of CSCs. Indeed, double knockout of DNA methyltransferase 1 (DNMT1) and DNA methyltransferase 3b (DNMT3b) in colon cancer cell line HCT116 resulted in loss of >95% DNA Methylation and complete loss of tumorigenicity both in vitro and in vivo. These data suggest that DNA Methylation is critical for maintenance of the colon CSC population, and a combination of classical chemotherapeutic drugs and DNA Methylation inhibitors may be an effective treatment of colon cancer.

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A Molecular Screening Approach to Identify and Characterize Inhibitors of Glioblastoma Stem Cells

Cited by 80 publications

References 44 publications

Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma

Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma

N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation

Enrichment and Selective Targeting of Cancer Stem Cells in Colorectal Cancer Cell Lines

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