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9.9
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Cells
Special Issues
Therapeutic Targets in Glioblastoma
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Therapeutic Targets in Glioblastoma

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 28 March 2025 | Viewed by 2025

Special Issue Editors

Dr. Candice Mazewski

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Genetics, Midwestern University, 555 31st St., Downers Grove, IL 60515, USA
Interests: glioblastoma; colorectal cancer; solid tumors; signaling targets; complementary medicine; nutrient-sensing; nutrition; plants; polyphenols; bioactives; microbiome; gut–brain axis
Dr. Frank Eckerdt

E-Mail Website
Guest Editor
1. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA
2. Division of Hematology-Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA
Interests: cancer biology; cell signaling; signal transduction; cancer stem cells; neuro-oncology; cell biology; cell division; clinical research; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glioblastoma (grade 4 brain cancer) is among the most difficult cancers to treat due in part to its high tumor heterogeneity and the protective blood–brain barrier limiting tumor penetration by therapeutics. Despite ongoing efforts, enhanced therapeutic targeting in glioblastoma has remained elusive, and a dismal 5-year survival rate persists. Expanding our understanding of the signaling changes in glioblastoma cells and the highly plastic glioma stem cell population is critical for developing more effective treatment options. Analyzing alternative targets and approaches is necessary to develop innovative therapeutic options that improve overall survival for glioblastoma patients.

For this Special Issue, we invite submissions in the form of original research articles and reviews that explore signaling dynamics and therapeutic strategies in glioblastoma. Topics may include signaling alterations linked to glioblastoma initiation, progression, and resistance and those affecting glioma stem cell populations. We also encourage submissions that explore alternative therapeutic approaches, including investigations of cell metabolism, nutrient-sensing pathways, and the impact of dietary components on signaling.

Dr. Candice Mazewski
Dr. Frank Eckerdt
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • glioblastoma
  • signaling targets
  • blood-brain-barrier
  • complementary and alternative medicine
  • combination therapy
  • glioma stem cells
  • progression
  • resistance
  • nutrient-sensing

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Published Papers (2 papers)

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Research

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26 pages, 18146 KiB  
Article
Trying to Kill a Killer; Impressive Killing of Patient Derived Glioblastoma Cultures Using NK-92 Natural Killer Cells Reveals Both Sensitive and Highly Resistant Glioblastoma Cells
by Jane Yu, Hyeon Joo Kim, Jordyn Reinecke, James Hucklesby, Tennille Read, Akshata Anchan, Catherine E. Angel and Euan Scott Graham
Cells 2025, 14(1), 53; https://doi.org/10.3390/cells14010053 - 5 Jan 2025
Viewed by 811
Abstract
The overall goal of this work was to assess the ability of Natural Killer cells to kill cultures of patient-derived glioblastoma cells. Herein we report impressive levels of NK-92 mediated killing of various patient-derived glioblastoma cultures observed at ET (effector: target) ratios of [...] Read more.
The overall goal of this work was to assess the ability of Natural Killer cells to kill cultures of patient-derived glioblastoma cells. Herein we report impressive levels of NK-92 mediated killing of various patient-derived glioblastoma cultures observed at ET (effector: target) ratios of 5:1 and 1:1. This enabled direct comparison of the degree of glioblastoma cell loss across a broader range of glioblastoma cultures. Importantly, even at high ET ratios of 5:1, there are always subpopulations of glioblastoma cells that prove very challenging to kill that evade the NK-92 cells. Of value in this study has been the application of ECIS (Electric Cell–Substrate Impedance Sensing) biosensor technology to monitor the glioblastoma cells in real-time, enabling temporal assessment of the NK-92 cells. ECIS has been powerful in revealing that at higher ET ratios, the glioblastoma cells are acutely sensitive to the NK-92 cells, and the observed glioblastoma cell death is supported by the high-content imaging data. Moreover, long-term ECIS experiments reveal that the surviving glioblastoma cells were then able to grow and reseed the culture, which was evident 300–500 h after the addition of the NK-92 cells. This was observed for multiple glioblastoma lines. In addition, our imaging provides evidence that some NK-92 cells appear to be compromised early, which would be consistent with potent evasive mechanisms by the glioblastoma tumour cells. This research strongly highlights the potential for NK-92 cells to kill glioblastoma tumour cells and provides a basis to identify the mechanism utilised by the surviving glioblastoma cells that we now need to target to achieve maximal cytolysis of the resistant glioblastoma cells. It is survival of the highly resistant glioblastoma clones that results in tumour relapse. Full article
(This article belongs to the Special Issue Therapeutic Targets in Glioblastoma)
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Figure 1

Figure 1
<p>NK-92 mediated glioblastoma cell loss. Imaging-based quantification of glioblastoma cell loss following co-culture with NK-92 cells. NK-92 cells were added at ET ratios of 1:5, 1:1 and 5:1 as indicated in the colour coded key. Data show glioblastoma cell loss for four different patient-derived glioblastoma cultures (NZB11, NZB12, NZB14 and NZB15). Each independent experiment was conducted 3–5 times. Each dot on the graph represents the average cell loss calculated from 27 to 36 images per treatment in a single experiment (see Methods section). The 100% dotted line represents the control glioblastoma cell counts. Thus, 25% “surviving” cells means 75% of the glioblastoma cells have been lost. Statistical comparisons were conducted (see Methods) with the treatment group and control group. Significance is shown where the <span class="html-italic">p</span>-value = 0.05 (*), 0.01 (**) and 0.001 (***).</p> Full article ">Figure 2
<p><b>NBZ11 glioblastoma cell loss.</b> Imaging-based quantification of glioblastoma cell loss following co-culture with NK-92 cells. NK-92 cells were added at ET ratios of 1:5, 1:1 and 5:1 as indicated in the colour coded key. The images are from a single representative experiment in the series, which is identified in the quantification graph. The symbol in (<b>a</b>) is highlighted with a black outline. (<b>b</b>) In these images the glioblastoma cells are green (actin), and the NK-92 cells are red. Nuclei are counterstained with Hoechst. Note the general lack of adherent NK-92 cells (red). Time represents the duration of co-culture for each respective E:T ratio.</p> Full article ">Figure 3
<p><b>NBZ12 glioblastoma cell loss.</b> Imaging-based quantification of glioblastoma cell loss following co-culture with NK-92 cells. NK-92 cells were added at ET ratios of 1:5, 1:1 and 5:1 as indicated in the colour coded key. The images are from a single representative experiment in the series, which is identified in the quantification graph, where the symbol in (<b>a</b>) is highlighted with a black outline. (<b>b</b>) In these images the glioblastoma cells are green (actin), and the NK-92 cells are red. Nuclei are counterstained with Hoechst. Time represents the duration of co-culture for each respective E:T ratio.</p> Full article ">Figure 4
<p><b>NBZ14 glioblastoma cell loss.</b> Imaging-based quantification of glioblastoma cell loss following co-culture with NK-92 cells. NK-92 cells were added at ET ratios of 1:5, 1:1 and 5:1 as indicated in the colour coded key. The images are from a single representative experiment, which is identified in the quantification graph, where the symbol in (<b>a</b>) is highlighted with a black outline. (<b>b</b>) In these images the glioblastoma cells are green (actin). Note the highly variable levels of actin intensity across the NZB14 culture. The NK-92 cells are red. Note the greater adhesion of NK-92 to the NZB14 culture, especially at 2 h post addition. Nuclei are counterstained with Hoechst. Time represents the duration of co-culture for each respective E:T ratio.</p> Full article ">Figure 5
<p><b>NBZ15 glioblastoma cell loss.</b> Imaging-based quantification of glioblastoma cell loss following co-culture with NK-92 cells. NK-92 cells were added at ET ratios of 1:5, 1:1 and 5:1 as indicated in the colour coded key. The images are from a single representative experiment, which is identified in the quantification graph, where the symbol in (<b>a</b>) is highlighted with a black outline. (<b>b</b>) In these images the glioblastoma cells are green (actin). Note the highly variable NZB15 morphology and clustering. The NK-92 cells are red. Nuclei are counterstained with Hoechst (blue). Time represents the duration of co-culture for each respective E:T ratio.</p> Full article ">Figure 6
<p><b>Real-time biosensor-based assessment of NK-92 effects on the glioblastoma cultures.</b> ECIS biosensor technology measures the relative adhesion strength of the glioblastoma culture and indicates when the adherent behaviour of the glioblastoma cells changes. The resistive value is a measure of the glioblastoma adhesion across the ECIS arrays, where stronger net adhesion results in greater resistance. The grey line is the resistance in the absence of cells referred to as the cell-free resistance (around 1600–1700 ohms). NK-92 cells were added to glioblastoma cultures at ~48 h post seeding into ECIS 1E+ plates, as indicated by the black arrows. The greater the reduction in resistance following the addition of the NK-92, the more cellular adhesion has been lost. The temporal nature of ECIS reveals whether the loss in adhesion is sustained or transient, where sustained loss is consistent with cell compromise and death. These data are from independent experiments, representative of at least 3–4 independent experiments. Statistical comparison was conducted at the time points indicated by the vertical dotted lines representing 2 h, 4 h and 24 h post addition of the NK-92 cells. Statistical significance is shown where the <span class="html-italic">p</span>-value = 0.001 (***).</p> Full article ">Figure 7
<p><b>Evidence of NZB11 glioblastoma cell death.</b> Images from NZB11 cultures two hours after NK-92 cell addition. Control glioblastoma cells are shown in the left panels where glioblastoma cells are green with Hoechst-stained nuclei; note the uniform nuclei and intact actin structures. In the right-side panels, the white arrows point to abnormal NZB11 nuclei, and the red arrows point to CD45-positive puncta and debris from the NK-92 cells. Karyorrhectic nuclei are evident, indicative of early signs of glioblastoma cell death. These images were acquired 2 h after NK-92 addition.</p> Full article ">Figure 8
<p><b>Early evidence of NZB14 glioblastoma cell compromise.</b> Images from NZB14 cultures 2–4 h after NK-92 addition. Control glioblastoma cells are shown in the top panels where glioblastoma cells are green with Hoechst-stained nuclei. Note the uniform nuclei and intact actin structures. The lower panels show NK-92 images from 1:1 ratio at 2 h and 4 h, respectively. CD45 staining (red) indicates the NK-92 cells. The white arrows point to abnormal NZB14 nuclei, and the red arrows point to CD45 positive puncta and debris from the NK-92 cells. After 2–4 h, many of the glioblastoma cells have abnormally shaped nuclei that appear karyorrhectic and in small puncta. This is indicative of early signs of glioblastoma cell death. These images were acquired 2–4 h after NK-92 addition.</p> Full article ">Figure 9
<p><b>Early evidence of NZB15 glioblastoma cell compromise.</b> Images from NZB15 cultures 2 h after NK-92 addition (1:1 ratio). Control glioblastoma cells are shown in the top left panel where glioblastoma cells are green with Hoechst-stained nuclei. CD45 staining (red) indicates the NK-92 cells. The white arrows point to abnormal NZB15 nuclei, and the red arrows point to CD45 positive puncta and debris from the NK-92 cells. Numerous glioblastoma cells have abnormally shaped nuclei that appear karyorrhectic and adjacent small DNA puncta. This is indicative of early signs of glioblastoma cell death. These images were acquired 2 h after NK-92 addition.</p> Full article ">Figure 10
<p><b>Evidence of NK-92 cell-death 24 h after their addition to the glioblastoma cultures.</b> The NK-92 cells are counterstained with CD45 (red). Some healthy/intact NK-92 cells are evident and highlighted with the red arrows. However, there are numerous examples of NK-92 cells with abnormal disintegrated nuclei, highlighted by the white arrows. These nuclei are indicative of NK-92 cells that are dying. There is also a considerable amount of CD45 stained puncta (red), which may be from dead NK-92 cells. The glioblastoma cells are counterstained green with Actin Ready probes. These images were acquired 24 h after NK-92 addition.</p> Full article ">Figure 11
<p><b>Long-term ECIS experiments demonstrate regrowth of the glioblastoma cultures.</b> ECIS biosensor experiments were conducted over 300–400 h to see whether the surviving glioblastoma cells were capable of regrowth. Data show the regrowth of the glioblastoma cells post addition of NK-92 cells at the 5:1 ratio (red curve), which resulted in the initial loss of most of the glioblastoma cells. Some regrowth was observed for all cultures. The time of NK-92 addition is indicated by the blue arrow. The black curve is the control media treated glioblastoma cells. These longer-term experiments are representative of 3 independent repeats.</p> Full article ">Figure 12
<p><b>Assessment of long-term regrowth from surviving glioblastoma cells following NK-92 mediated killing.</b> On the ECIS graphs (<b>a</b>) the time scale is from time 0 and NK-92 cells were added 48 h into the culture. (<b>b</b>) Cultures were assessed at designated time points to visualise the glioblastoma cell regrowth. This was 24 h, 312 h and ~450 h after NK-92 addition. Glioblastoma cells were stained with actin-green and nuclei with Hoechst. NK-92 cells are red (CD45 positive). Following the initial glioblastoma loss, substantial regrowth is evident. In the zoom images, the solid red arrows indicate intact NK-92 cells, whereas the dashed red arrows indicate NK-92 debris. White scale bars represent 50 µm.</p> Full article ">Figure 13
<p><b>Regrowth of NZB12 from surviving glioblastoma cells following NK-92 mediated killing.</b> (<b>a</b>) The ECIS graphs indicate NZB12 regrowth within ~300 post NK-92 addition. (<b>b</b>) Cultures were assessed at 24 h, 312 h and ~450 h after NK-92 addition. Glioblastoma cells were stained with actin-green and nuclei with Hoechst. NK-92 cells are red (CD45 positive). Note the abundance of the CD45 positive NK-92 puncta still present in the 312 h images. Many are not intact viable NK-92 cells and are gone by 450 h. Imaging panels support this observation for the 5:1 and 1:1 ratios. Following the initial glioblastoma loss, substantial regrowth is evident. White scale bars represent 50 µm.</p> Full article ">Figure 14
<p><b>Partial regrowth of NZB14 from surviving glioblastoma cells following NK-92 mediated killing.</b> (<b>a</b>) The ECIS curves indicate modest NBZ14 regrowth and the imaging panels support the ECIS data. (<b>b</b>) Cultures were assessed at 24 h, 312 h and ~450 h after NK-92 addition. Glioblastoma cells were stained with actin-green and nuclei with Hoechst. NK-92 cells are red (CD45 positive). Note the abundance of the CD45 positive NK-92 puncta present in the 312 h images, which are mostly gone by 450 h. White scale bars represent 50 µm.</p> Full article ">Figure 15
<p><b>Partial regrowth of NZB15 from surviving glioblastoma cells following NK-92 mediated killing.</b> (<b>a</b>) The ECIS curves indicate slow NBZ15 regrowth following 5:1 NK-92 killing. (<b>b</b>) Cultures were assessed at 24 h, 312 h and ~450 h after NK-92 addition. Glioblastoma cells were stained with actin-green and nuclei with Hoechst. NK-92 cells are red (CD45 positive). The imaging panels support the ECIS data. Note the very large NZB15 glioblastoma cells present in the zoom panels. Note the abundance of the CD45 positive NK-92 puncta present in the 312 h images, which are still present at 450 h. White scale bars represent 50 µm.</p> Full article ">

Review

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25 pages, 3398 KiB  
Review
Harnessing Arsenic Derivatives and Natural Agents for Enhanced Glioblastoma Therapy
by Bo Yuan and Hidetomo Kikuchi
Cells 2024, 13(24), 2138; https://doi.org/10.3390/cells13242138 - 23 Dec 2024
Viewed by 865
Abstract
Glioblastoma (GBM) is the most common and lethal intracranial tumor in adults. Despite advances in the understanding of the molecular events responsible for disease development and progression, survival rates and mortality statistics for GBM patients have been virtually unchanged for decades and chemotherapeutic [...] Read more.
Glioblastoma (GBM) is the most common and lethal intracranial tumor in adults. Despite advances in the understanding of the molecular events responsible for disease development and progression, survival rates and mortality statistics for GBM patients have been virtually unchanged for decades and chemotherapeutic drugs used to treat GBM are limited. Arsenic derivatives, known as highly effective anticancer agents for leukemia therapy, has been demonstrated to exhibit cytocidal effects toward GBM cells by inducing cell death, cell cycle arrest, inhibition of migration/invasion, and angiogenesis. Differentiation induction of glioma stem-like cells (GSCs) and inhibition of neurosphere formation have also been attributed to the cytotoxicity of arsenic derivatives. Intriguingly, similar cytotoxic effects against GBM cells and GSCs have also been observed in natural agents such as anthocyanidins, tetrandrine, and bufadienolides. In the current review, we highlight the available data on the molecular mechanisms underlying the multifaceted anticancer activity of arsenic compounds and natural agents against cancer cells, especially focusing on GBM cells and GCSs. We also outline possible strategies for developing anticancer therapy by combining natural agents and arsenic compounds, as well as temozolomide, an alkylating agent used to treat GBM, in terms of improvement of chemotherapy sensitivity and minimization of side effects. Full article
(This article belongs to the Special Issue Therapeutic Targets in Glioblastoma)
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Figure 1

Figure 1
<p>Structural formula of different arsenic compounds.</p> Full article ">Figure 2
<p>Schematic illustration of the molecular mechanism underlying the pleiotropic anticancer activity of As<sub>2</sub>O<sub>3</sub> against GBM cells. As<sub>2</sub>O<sub>3</sub> primarily targets mitochondria by inducing loss of mitochondrial membrane potential (ΔΨm) associated with an imbalance of the Bax/Bcl-2 ratio, as well as upregulation of mitoferrin-2, which in turn causes ROS accumulation, ultimately leads to apoptosis induction and/or cell cycle arrest. Impacts of As<sub>2</sub>O<sub>3</sub> on ROS elimination system such as anti-oxidative enzymes and GSH also contribute to ROS accumulation, which has been closely linked to DNA damage and inhibition of human telomerase reverse transcriptase (hTERT). Silencing of mitochondrial glutaminase (GA) and xeroderma pigmentosum group C (XPC), inhibition of Nrf2/HO-1, and knockdown of X box-binding protein-1 (XBP1), all of which contribute to maintain the redox balance, sensitize GBM cells to As<sub>2</sub>O<sub>3</sub>. As<sub>2</sub>O<sub>3</sub> also triggers necrotic and autophagic cell death as evidenced by LDH leakage and restoration of cell viability by the addition of autophagy inhibitors, respectively. Of note, As<sub>2</sub>O<sub>3</sub> triggers a cytocidal effect against GBM cells regardless of different p53 status (p53-w/p53-mut). Inhibition of the Notch1 signaling pathway and downregulation of VEGF, along with suppression of MMPs (MMP-2 and MMP-9), contribute to As<sub>2</sub>O<sub>3</sub>-mediated cell cycle arrest, inhibition of migration/invasion, and angiogenesis.</p> Full article ">Figure 3
<p>Schematic illustration of the molecular mechanism underlying the pleiotropic anticancer activity of As<sub>2</sub>O<sub>3</sub> against GSCs. Besides apoptosis induction, As<sub>2</sub>O<sub>3</sub> suppresses the Hedgehog/Notch1 signaling pathway and downregulates CD133/Nestin/Hes 1, all of which highly express in GSCs, leading to inhibition of neurosphere formation and differentiation of GSCs. In addition, upregulation of TujI (β-tubulin III), a neuronal differentiation marker, is attributed to the differentiation-inducing activity of As<sub>2</sub>O<sub>3</sub>.</p> Full article ">Figure 4
<p>Chemical structures of anthocyanidins.</p> Full article ">Figure 5
<p>Chemical structure of tetrandrine.</p> Full article ">Figure 6
<p>Schematic illustration of the molecular mechanism underlying the pleiotropic anticancer activity of tetrandrine against GBM cells and GSCs. Besides autophagic cell death induction, tetrandrine not only modulates the expression of pro-apoptotic (Bax and Bid) and anti-apoptotic proteins (Bcl-2, Mcl-1, XIAP), but also directly induces apoptosis-inducing factor (AIF), resulting in apoptosis induction. ROS accumulation, because of tetrandrine-meditated mitochondrial dysfunction, can activate MAPKs (p-38 and JNK) and consequently induce cell death. In addition, tetrandrine suppresses EGFR, VEGF, and their downstream targets, resulting in inhibition of migration/invasion and angiogenesis, as well as cell cycle arrest in GBM cells. Tetrandrine also can suppress the Wnt/β-catenin singling pathway, inhibit the nuclear translocation of β-catenin, and ultimately repress neurosphere formation of GSCs. Importantly, tetrandrine has been reported to inhibit a multidrug resistance protein, P-glycoprotein (P-gp), and consequently reverses multidrug resistances, which are closely linked to poor prognosis of GBM.</p> Full article ">Figure 7
<p>Chemical structures of bufadienolides.</p> Full article ">
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