Glioblastoma entities express subtle differences in molecular composition and response to treatment

Balça-Silva, Joana; Matias, Diana; Carmo, Anália do; Dubois, Luiz Gustavo; Gonçalves, Ana Cristina; Girão, Henrique; Canêdo, Nathalie Henriques Silva; Correia, Ana Helena Pereira; Souza, Jorge Marcondes de; Sarmento‐Ribeiro, Ana Bela; Lopes, María Celeste; Moura‐Neto, Vivaldo

doi:10.3892/or.2017.5799

Cited by 23 publications

(29 citation statements)

References 44 publications

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“…These cells were maintained in Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/F12), supplemented with 10% of fetal bovine serum (FBS), and maintained at 37°C in an atmosphere containing 95% air and 5% CO 2 . For the assays performed using glioma stem cells (GSCs), the cells were maintained in culture according to our previous studies [5]. The cells were plated in a defined NS34 serumfree medium supplemented with sodium pyruvate, glutamine, B-27, G-5 and, N-2 supplements, penicillin and streptomycin [5] to maintain the GSCs properties.…”

Section: Maintenance Of Cell Line Culturesmentioning

confidence: 99%

“…For the assays performed using glioma stem cells (GSCs), the cells were maintained in culture according to our previous studies [5]. The cells were plated in a defined NS34 serumfree medium supplemented with sodium pyruvate, glutamine, B-27, G-5 and, N-2 supplements, penicillin and streptomycin [5] to maintain the GSCs properties.…”

Section: Maintenance Of Cell Line Culturesmentioning

confidence: 99%

“…Since the presence of GSCs is known to be one of the main reasons for the resistance to radio-and chemotherapy [34], we hypothesized that the remaining cells after the combined treatment could have acquired stem cell properties. GSCs share similar characteristics as stem cells by expressing pluripotent genes, such as SOX-2 or OCT-4, transcription factors extremely important for the maintenance of stemness of the cells [5,35], ability to form clones and floating spheres, for instance [5]. To test our 11 hypothesis, the nuclear expression of SOX-2 and OCT-4 in those cells was evaluated.…”

Section: The Combined Treatment With Cyclopamine and Tmz Increases Thmentioning

confidence: 99%

“…GBM radio and chemoresistance is related to several mechanisms, such as the presence of glioma stem cells (GSCs), for instance [5]. Some studies have shown that TMZ is inefficient in inducing GSC death [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…Here, we analyzed if the inhibition of the SHH pathway with cyclopamine could potentiate the TMZ effect in different GBM cell lines in vitro. 5 All culture reagents as well as the secondary antibodies, conjugated to Alexa Fluor 488, 546 and HRP, Fluoromount-G, BCA TM Protein Assay kit, Super Signal™ West Pico or West Femto Chemiluminescent Substrate, Trizol, oligodT (12)(13)(14)(15)(16)(17)(18) Hybond-P polyvinylidene difluoride (PVDF) transfer membrane was obtained from BioRad Laboratories (Berkeley, CA, USA). Anti-PTCH1, anti-SHH, anti-GAPDH were obtained from Abcam (Cambridge, MA, USA).…”

Section: Introductionmentioning

confidence: 99%

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Cyclopamine sensitizes Glioblastoma cells to Temozolomide treatment through Sonic Hedgehog pathway

Carballo

Matias

Honorato

et al. 2020

Preprint

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AimGlioblastoma is an extremely aggressive glioma, resistant to radio and chemotherapy usually performed with temozolomide. One of the main reasons for glioblastoma resistance to conventional therapies is due to the presence of cancer stem-like cells. These cells could recapitulate some signaling pathways important for embryonic development, such as Sonic hedgehog. Here, we investigated if the inhibitor of the Sonic hedgehog pathway, cyclopamine, could potentiate the temozolomide effect in cancer stem-like cells and glioblastoma cell lines in vitro.Main methodsThe viability of glioblastoma cells exposed to cyclopamine and temozolomide treatment was evaluated by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay while the induction of apoptosis was assessed by western blot. The stemness properties of glioma cells were verified by clonogenic and differentiation assay and the expression of stem cell markers were measured by fluorescence microscopy and western blot.Key findingsThe glioblastoma viability was reduced by cyclopamine treatment. Cyclopamine potentiated temozolomide treatment in glioblastoma cell lines by inducing apoptosis through activation of caspase-3 cleaved. Conversely, the combined treatment of cyclopamine and temozolomide potentiated the stemness properties of glioblastoma cells by inducing the expression of SOX-2 and OCT-4.SignificanceCyclopamine plays an effect on glioblastoma cell lines but also sensibilize them to temozolomide treatment. Thus, first-line treatment with Sonic hedgehog inhibitor followed by temozolomide could be used as a new therapeutic strategy for glioblastoma patients.

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Section: Maintenance Of Cell Line Culturesmentioning

confidence: 99%

Section: Maintenance Of Cell Line Culturesmentioning

confidence: 99%

Section: The Combined Treatment With Cyclopamine and Tmz Increases Thmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cyclopamine sensitizes Glioblastoma cells to Temozolomide treatment through Sonic Hedgehog pathway

Carballo

Matias

Honorato

et al. 2020

Preprint

Self Cite

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Role of Sonic hedgehog signaling in cell cycle, oxidative stress, and autophagy of temozolomide resistant glioblastoma

Honorato

Hauser‐Davis

Saggioro

et al. 2019

Journal Cellular Physiology

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The first‐line chemotherapy treatment for Glioblastoma (GBM) ‐ the most aggressive and frequent brain tumor ‐ is temozolomide (TMZ). The Sonic hedgehog (SHH) pathway is involved with GBM tumorigenesis and TMZ chemoresistance. The role of SHH pathway inhibition in the potentiation of TMZ's effects using T98G, U251, and GBM11 cell lines is investigated herein. The combination of GANT‐61 and TMZ over 72 hr suggested a synergistic effect. All TMZ‐resistant cell lines displayed a significant decrease in cell viability, increased DNA fragmentation and loss of membrane integrity. For T98G cells, G2/M arrest was observed, while U251 cells presented a significant increase in reactive oxygen species production and catalase activity. All the cell lines presented acidic vesicles formation correlated to Beclin‐1 overexpression. The combined treatment also enhanced GLI1 expression, indicating the presence of select resistant cells. The selective inhibition of the SHH pathway potentiated the cytotoxic effect of TMZ, thus becoming a promising in vitro strategy for GBM treatment.

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CCL21-CCR7 signaling promotes microglia/macrophage recruitment and chemotherapy resistance in glioblastoma

Geraldo

García

et al. 2023

Cell. Mol. Life Sci.

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Glioblastoma (GBM) is the most common and fatal primary tumor of the central nervous system (CNS) and current treatments have limited success. Chemokine signaling regulates both malignant cells and stromal cells of the tumor microenvironment (TME), constituting a potential therapeutic target against brain cancers. Here, we investigated the C–C chemokine receptor type 7 (CCR7) and the chemokine (C–C-motif) ligand 21 (CCL21) for their expression and function in human GBM and then assessed their therapeutic potential in preclinical mouse GBM models. In GBM patients, CCR7 expression positively associated with a poor survival. CCL21–CCR7 signaling was shown to regulate tumor cell migration and proliferation while also controlling tumor associated microglia/macrophage recruitment and VEGF-A production, thereby controlling vascular dysmorphia. Inhibition of CCL21–CCR7 signaling led to an increased sensitivity to temozolomide-induced tumor cell death. Collectively, our data indicate that drug targeting of CCL21–CCR7 signaling in tumor and TME cells is a therapeutic option against GBM.

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Glioblastoma entities express subtle differences in molecular composition and response to treatment

Cited by 23 publications

References 44 publications

Cyclopamine sensitizes Glioblastoma cells to Temozolomide treatment through Sonic Hedgehog pathway

Cyclopamine sensitizes Glioblastoma cells to Temozolomide treatment through Sonic Hedgehog pathway

Role of Sonic hedgehog signaling in cell cycle, oxidative stress, and autophagy of temozolomide resistant glioblastoma

CCL21-CCR7 signaling promotes microglia/macrophage recruitment and chemotherapy resistance in glioblastoma

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