DNA inhibitors for the treatment of brain tumors

Lisi, Lucia; Chiavari, Marta; Ciotti, Gabriella Maria Pia; Lacal, Pedro Miguel; Navarra, Pierluigi; Graziani, Grazia

doi:10.1080/17425255.2020.1729352

Cited by 4 publications

(3 citation statements)

References 121 publications

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“…Glioblastoma (GB-grade IV glioma) is the most aggressive and common cancer of the central nervous system in adults, with over 10,000 new cases in the United States per year [1]. The first-line treatment consists in a multimodal approach with surgical resection, when possible, followed by radiation therapy, plus concomitant and adjuvant chemotherapy with temozolomide [2]. However due to its invasiveness and infiltrative behavior, GB is characterized by a median overall survival of only 14-16 months.…”

Section: Introductionmentioning

confidence: 99%

PDIA3 Expression in Glioblastoma Modulates Macrophage/Microglia Pro-Tumor Activation

Chiavari¹,

Ciotti²,

Canonico

et al. 2020

IJMS

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The glioblastoma (GB) microenvironment includes cells of the innate immune system identified as glioma-associated microglia/macrophages (GAMs) that are still poorly characterized. A potential role on the mechanisms regulating GAM activity might be played by the endoplasmic reticulum protein ERp57/PDIA3 (protein disulfide-isomerase A3), the modulation of which has been reported in a variety of cancers. Moreover, by using The Cancer Genome Atlas database, we found that overexpression of PDIA3 correlated with about 55% reduction of overall survival of glioma patients. Therefore, we analyzed the expression of ERp57/PDIA3 using specimens obtained after surgery from 18 GB patients. Immunohistochemical analysis of tumor samples revealed ERp57/PDIA3 expression in GB cells as well as in GAMs. The ERp57/PDIA3 levels were higher in GAMs than in the microglia present in the surrounding parenchyma. Therefore, we studied the role of PDIA3 modulation in microglia–glioma interaction, based on the ability of conditioned media collected from human GB cells to induce the activation of microglial cells. The results indicated that reduced PDIA3 expression/activity in GB cells significantly limited the microglia pro-tumor polarization towards the M2 phenotype and the production of pro-inflammatory factors. Our data support a role of PDIA3 expression in GB-mediated protumor activation of microglia.

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Section: Introductionmentioning

confidence: 99%

PDIA3 Expression in Glioblastoma Modulates Macrophage/Microglia Pro-Tumor Activation

Chiavari¹,

Ciotti²,

Canonico

et al. 2020

IJMS

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“…However, it does not affect the overall survival in patients [ 8 ]. Another approach to new therapeutic strategies in GB is the application of already known anti-cancer agents, such as topoisomerase inhibitors (e.g., doxorubicin or etoposide) [ 9 ]. Their efficacy has been proved in pre-clinical and clinical studies, mainly in combined treatment with other chemotherapeutics [ 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Chemosensitization of U-87 MG Glioblastoma Cells by Neobavaisoflavone towards Doxorubicin and Etoposide

Maszczyk

Banach

Karkoszka

et al. 2022

IJMS

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Glioblastoma (GB) is the most common type of glioma, which is distinguished by high mortality. Due to the rapid progression of the tumor and drug resistance, the treatment is often ineffective. The development of novel therapies in a big part concerns the application of anti-cancer agents already used in clinical practice, unfortunately often with limited effects. This could be overcome through the use of compounds that possess chemosensitizing properties. In our previous work, it has been shown that neobavaisoflavone (NBIF) enhances the in vitro activity of doxorubicin in GB cells. The aim of this study was a further investigation of the possible chemosensitizing effects of this isoflavone. The experimental panel involving image cytometry techniques, such as count assay, examination of mitochondrial membrane potential, Annexin V assay, and cell cycle analysis, was performed in human glioblastoma U-87 MG cells and normal human astrocytes (NHA) treated with NBIF, doxorubicin, etoposide, and their mixes with NBIF. NBIF in co-treatment with etoposide or doxorubicin caused an increase in the population of apoptotic cells and prompted alterations in the cell cycle. NBIF enhances the pro-apoptotic activity of etoposide and doxorubicin in U-87 MG cells, which could be a sign of the chemosensitizing properties of the isoflavone.

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“…Glioblastoma (GB -grade IV glioma) is the most aggressive and common cancer of central nervous system in adults with over 10,000 new cases in United States per year [1]. The rst-line treatment consists in a multimodal approach with surgical resection, when possible, followed by radiation therapy and concomitant and adjuvant chemotherapy with Temozolomide [2]. However due to its invasiveness and in ltrative behavior, the GB is characterized by an overall survival of 14-16 months.…”

Section: Introductionmentioning

confidence: 99%

PDIA3 Reduce Glioma-associated Macrophage/microglia Pro-tumor Activation trough IL-6-STAT3-PDIA3 Pathway.

Chiavari

Ciotti

Canonico

et al. 2020

Preprint

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Background: Glioblastoma (GB - grade IV glioma) is the most aggressive and common cancer of central nervous system with an overall survival of 14-16 months. The GB tumor microenvironment includes cells of the innate immune system identified as glioma-associated microglia/macrophages (GAMs). It is known that between GAMs and GB cells there is a double interaction, but the role of GAMs is still poorly characterized. The endoplasmic reticulum (ER) protein ERp57, also known as PDIA3, is a thiol oxidoreductase with main function related on glycoprotein folding in endoplasmic reticulum. However, PDIA3 shows different functions. In fact, the various subcellular localizations and binding partners of PDIA3 affect numerous physiological processes and diseases: different regulation and modulation of PDIA3 has been reported in multiple pathologies including neurodegenerative diseases and cancer. Methods: In the present work, we evaluated in both GB cells and microglia-macrophage cells the expression of PDIA3 using specimens collected after surgical from 18 GB patients. In addition, we studied in vitro microglia-glioma interaction to determine the role of PDIA3 in viability and the activation of both GB and microglia cells. The study was carried using PDIA3-silenced T98G cells and/or using a pharmacological inhibitor of PDIA3 activity (Punicalagin-PUN).Results: We initially investigated the role of the PDIA3 in GB survival by inquiring The Cancer Genome Atlas dataset. The results indicated that 352 out of 690 patients reported over-expression of PDIA3, which significantly correlated with a ~55% reduction of overall survival. Subsequently, for the first time, we investigated the PDIA3 expression in the tumor and the nearby parenchyma of 18 GB patients and our data showed a significant upregulation (15% vs 10%) of ERp57/PDIA3 in GAMs of tumor specimens respect the microglia present in parenchyma. In addition, we show that conditioned medium (CMs) obtained from both wild type T98G and PDIA3 silenced T98G induced an activation of microglia cells, but the PDIA3 silenced-T98G CMs significant limited the microglia pro-tumor activation probably through a IL-6-STAT3-PDIA3 dependent mechanism. Conclusion: Our data support the relevant role of PDIA3 expression in GB pathology and link the different activation of microglia to a mechanism a IL-6-STAT3-PDIA3 dependent.

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DNA inhibitors for the treatment of brain tumors

Cited by 4 publications

References 121 publications

PDIA3 Expression in Glioblastoma Modulates Macrophage/Microglia Pro-Tumor Activation

PDIA3 Expression in Glioblastoma Modulates Macrophage/Microglia Pro-Tumor Activation

Chemosensitization of U-87 MG Glioblastoma Cells by Neobavaisoflavone towards Doxorubicin and Etoposide

PDIA3 Reduce Glioma-associated Macrophage/microglia Pro-tumor Activation trough IL-6-STAT3-PDIA3 Pathway.

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