Targeting Cancer Cells With the Natural Compound Obtusaquinone

Badr, Christian E.; Hoppe, Stéphanie van; Dumbuya, Hawasatu; Tjon-Kon-Fat, Lee-Ann; Tannous, Bakhos A.

doi:10.1093/jnci/djt037

Cited by 20 publications

(26 citation statements)

References 24 publications

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“…Oxidative stress levels increased within the same treatment timeframe in U87 and primary GBM cells. Similar results have been reported from glioblastoma, prostate and colon cancer cell studies, where GSH scavenger treatment caused a reduction in GSH followed by an increase in ROS levels and apoptosis (Khan et al 2012;Badr et al 2013;Noh et al 2015). Q-PAC treatment likewise resulted in apoptosis, causing a concentration-dependent increase in caspase 3/7 activity in U87 and primary GBM cultures without affecting caspase activity in primary astrocytes.…”

Section: Discussionsupporting

confidence: 86%

“…GBM cells up-regulate GSH to compensate for their increased ROS production (Ogunrinu and Sontheimer 2010). Q-PAC and other anti-tumour drugs (including anti-GBM compounds) therefore target this mechanism as a possible treatment avenue (Alexandre et al 2006;Badr et al 2013;Kohsaka et al 2013;Noh et al 2015). In our mass spectrometry assay, while not being a kinetic assay, we confirmed that prodrug Q-PAC was able to undergo H 2 O 2 -induced oxidative cleavage of its boronate functionality to QM, 2-PCPA and QM-derived adducts.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, cancer cells survive high ROS by up-regulation of the ROS scavenger GSH (Ogunrinu and Sontheimer 2010). Both these prodrugs and other anti-cancer drugs therefore directly or indirectly target the GSH mechanism to further elevate intracellular ROS and kill their target cells (Alexandre et al 2006;Badr et al 2013;Kohsaka et al 2013;Noh et al 2015). However, cancercell-selective prodrugs based on the common LSD1 inhibitor trans-2-phenylcyclopropylamine (2-PCPA/tranylcypromine) are almost unexplored to date.…”

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confidence: 99%

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Novel dual‐action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine‐specific histone demethylase 1A inhibitor

Engel

Gee

Cross

et al. 2019

Journal of Neurochemistry

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Targeting epigenetic mechanisms has shown promise against several cancers but has so far been unsuccessful against glioblastoma ( GBM ). Altered histone 3 lysine 4 methylation and increased lysine‐specific histone demethylase 1A ( LSD 1) expression in GBM tumours nonetheless suggest that epigenetic mechanisms are involved in GBM . We engineered a dual‐action prodrug, which is activated by the high hydrogen peroxide levels associated with GBM cells. This quinone methide phenylaminecyclopropane prodrug releases the LSD 1 inhibitor 2‐phenylcyclopropylamine with the glutathione scavenger para ‐quinone methide to trigger apoptosis in GBM cells. Quinone methide phenylaminocyclopropane impaired GBM cell behaviours in two‐dimensional and three‐dimensional assays, and triggered cell apoptosis in several primary and immortal GBM cell cultures. These results support our double‐hit hypothesis of potentially targeting LSD 1 and quenching glutathione, in order to impair and kill GBM cells but not healthy astrocytes. Our data suggest this strategy is effective at selectively targeting GBM and potentially other types of cancers. Open science badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/ .

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Novel dual‐action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine‐specific histone demethylase 1A inhibitor

Engel

Gee

Cross

et al. 2019

Journal of Neurochemistry

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“…Single‐cell suspensions were stained with Annexin V‐Cy5 (Biovision Inc., Milpitas, CA, http://www.biovision.com) and PI. Cells were then analyzed using BD LSR II flow cytometer (BD biosciences, San Jose, CA, http://www.bdbiosciences.com) as previously described . Flow cytometry data were analyzed using Flowjo 7 (Flowjo, Ashland, OR, http://www.flowjo.com).…”

Section: Methodsmentioning

confidence: 99%

Systemic Anticancer Neural Stem Cells in Combination with a Cardiac Glycoside for Glioblastoma Therapy

et al. 2014

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The tumor-tropic properties of neural stem cells (NSCs) have been shown to serve as a novel strategy to deliver therapeutic genes to tumors. Recently, we have reported that the cardiac glycoside lanatoside C (Lan C) sensitizes glioma cells to the anticancer agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we engineered an FDA-approved human NSC line to synthesize and secrete TRAIL and the Gaussia luciferase (Gluc) blood reporter. We showed that upon systemic injection, these cells selectively migrate toward tumors in the mice brain across the blood-brain barrier, target invasive glioma stem-like cells, and induce tumor regression when combined with Lan C. Gluc blood assay revealed that 30% of NSCs survived 1 day postsystemic injection and around 0.5% of these cells remained viable after 5 weeks in glioma-bearing mice. This study demonstrates the potential of systemic injection of NSCs to deliver anticancer agents, such as TRAIL, which yields glioma regression when combined with Lan C.

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“…Spectrum Collection Library (MicroSource, Gaylordsville, CT) was designed to screen small compounds for anti-tumor chemotherapeutic agents, and obtusaquinone (one natural product) was identified to have pro-apoptotic effect on TSCs in vitro and to suppress tumor in vivo [20]. However, the suppression ratio was not as high as expected, and many new promising agents needed confirmation by clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Juglone induces apoptosis of tumor stem-like cells through ROS-p38 pathway in glioblastoma

Zhang

et al. 2017

BMC Neurol

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BackgroundJuglone is a natural pigment, which has cytotoxic effect against various human tumor cells. However, its cytotoxicity to glioma cells, especially to tumor stem-like cells (TSCs) has not been demonstrated.MethodsTSCs of glioma were enriched from U87 and two primary cells (SHG62, and SHG66) using serum-free medium supplemented with growth factors, including bFGF, EGF and B27. After treatment of juglone with gradient concentrations (0, 10, 20, and 40 μM), the viability and apoptosis of TSCs were evaluated by WST-8 assay and flow cytometry. Reactive oxygen species (ROS) was labeled by the cell-permeable fluorescent probe and detected with flow cytometry. ROS scavenger (NAC) and p38-MAPK inhibitor (SB203580) were applied to resist the cytotoxic effect. Caspase 9 cleavage and p38 phosphorylation (P-p38) were quantified by western blot. Juglone as well as temozolomide (TMZ) were administrated in intracranial xenografts and MR scan was performed every week to evaluate the anti-tumor effect in vivo.ResultsJuglone could obviously inhibit the proliferation of TSCs in glioma by decreasing cell viability (P < 0.01) and inducing apoptosis (P < 0.01), which was accompanied by increased caspase 9 cleavage in a dose-dependent manner (P < 0.01). In the meantime, juglone could generate ROS significantly and increase p38 phosphorylation (P < 0.01). In addition, pretreatment with ROS scavenger or p38-MAPK inhibitor could reverse juglone-induced cytotoxicity (P < 0.01). More importantly, juglone could also suppress tumor growth in vivo and improve the survival of U87-bearing mice compared with control (P < 0.05), although TMZ seemed to have better effect.ConclusionsJuglone could inhibit the growth of TSCs in gliomas through the activation of ROS-p38-MAPK pathway in vitro, and the anti-glioma effect was validated in vivo, which offers a potential therapeutic agent to gliomas.

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Targeting Cancer Cells With the Natural Compound Obtusaquinone

Abstract: Given its properties and efficacy in cancer killing, our results suggest that OBT is a promising cancer therapeutic.

Cited by 20 publications

References 24 publications

Novel dual‐action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine‐specific histone demethylase 1A inhibitor

Novel dual‐action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine‐specific histone demethylase 1A inhibitor

Systemic Anticancer Neural Stem Cells in Combination with a Cardiac Glycoside for Glioblastoma Therapy

Juglone induces apoptosis of tumor stem-like cells through ROS-p38 pathway in glioblastoma

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