Specific Cytostatic and Cytotoxic Effect of Dihydrochelerythrine in Glioblastoma Cells: Role of NF-κB/β-catenin and STAT3/IL-6 Pathways

Silva, Tereza C C; Lopes, Giselle Pinto de Faria; Menezes-Filho, Noélio de J; Oliveira, Diêgo Madureira de; Pereira, Ezequiel; Pitanga, Bruno Penas Seara; Costa, Rafael dos Santos; Velozo, Eudes da Silva; Freire, Songelí Menezes; Clarêncio, Jorge; Borges, Helena L.; Rehen, Stevens K.; Moura‐Neto, Vivaldo; Costa, Sílvia Lima

doi:10.2174/1871520618666180412122101

Cited by 6 publications

(5 citation statements)

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“…The physiological effects of the FAB treatment in viability and migration of GBM cells could involve different molecular pathways. Recently, Silva et al (2018) observed that the balance between STAT3 and pSTAT3 expression could promote a cell cycle arrest and different types of GBM cells treated with the alkaloid dihydrochelerythrine, which demonstrated cell death or survival fate. Hence, in this study, the expression of STAT3 was evaluated in GL‐15 and U373 cells treated with increasing concentrations of the flavonoid FAB for 72 h, as in viability and migration assays (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Reverted effect of mesenchymal stem cells in glioblastoma treated with agathisflavone and its selective antitumoral effect on cell viability, migration, and differentiation via STAT3

Nascimento

Santos

Silva

et al. 2020

Journal Cellular Physiology

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Glioblastoma is the most lethal tumor of the central nervous system, presenting a very poor prognostic, with a survival around 16 months. The interaction of mesenchymal stem cells and tumor cells has been studied, showing a bias in their role favoring or going against aggressiveness. Natural products such as flavonoids have showed their anticancer properties and the synergic potential with the activation of microenvironment cells to inhibit tumor progression. Agathisflavone is a flavonoid studied in neurodegenerative diseases and cancer. The present study investigated the effect of flavonoid in the viability of heterogeneous glioblastoma (GBM) cells considering a coculture or conditioned medium of mesenchymal stem cells (MSCs) effect, as well as the dose‐dependent effect of this flavonoid in tumor migration and differentiation via STAT3. Agathisflavone (3–10 μM) induced dose‐dependent toxicity to GL‐15 and U373 human GBM cells, since 24 h after treatments. It was not toxic to human MSC but modified the pattern of interaction with GBM cells. Agathisflavone also inhibited migration and increased differentiation of human GBM cells, associated with the reduction on the expression of STAT3. These results demonstrate that the flavonoid agathisflavone had a direct anti‐glioma effect. However, could be observed its effect in MSCs response that may have an impact in controlling GBM growth and aggressiveness, an important factor to consider for new therapies.

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Section: Resultsmentioning

confidence: 99%

Reverted effect of mesenchymal stem cells in glioblastoma treated with agathisflavone and its selective antitumoral effect on cell viability, migration, and differentiation via STAT3

Nascimento

Santos

Silva

et al. 2020

Journal Cellular Physiology

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“…STAT3 is activated by IL‐6 signaling in GBM, 25 where it is implicated in cell invasion, tumor progression, and resistance to radio‐ and chemotherapy 40,41 . Protein levels of both IL‐6 and phosphorylated STAT3 were decreased in all RBPJ‐silenced GBM cell lines we used.…”

Section: Discussionmentioning

confidence: 97%

RBPJ contributes to the malignancy of glioblastoma and induction of proneural‐mesenchymal transition via IL‐6‐STAT3 pathway

et al. 2020

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Notch signaling plays a pivotal role in many cancers, including glioblastoma (GBM). Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) is a key transcription factor of the Notch signaling pathway. Here, we interrogated the function of RBPJ in GBM. Firstly, RBPJ expression of GBM samples was examined. Then, we knocked down RBPJ expression in 2 GBM cell lines (U251 and T98) and 4 glioblastoma (GBM) stem‐like cell lines derived from surgical samples of GBM (KGS01, KGS07, KGS10 and KGS15) to investigate the effect on cell proliferation, invasion, stemness, and tumor formation ability. Expression of possible downstream targets of RBPJ was also assessed. RBPJ was overexpressed in the GBM samples, downregulation of RBPJ reduced cell proliferation and the invasion ability of U251 and T98 cells and cell proliferation ability and stemness of glioblastoma stem‐like cells (GSC) lines. These were accompanied by reduced IL‐6 expression, reduced activation of STAT3, and inhibited proneural‐mesenchymal transition (PMT). Tumor formation and PMT were also impaired by RBPJ knockdown in vivo. In conclusion, RBPJ promotes cell proliferation, invasion, stemness, and tumor initiation ability in GBM cells through enhanced activation of IL‐6‐STAT3 pathway and PMT, inhibition of RBPJ may constitute a prospective treatment for GBM.

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“…Another alkaloid structure, piperlongumine (Figure 6), appears to have anticancer properties via downregulating c-Met expression and NF-kB activity in renal, colon, lung, and prostate carcinoma cells (264)(265)(266)(267)(268). Harmine (269), fangchinoline (270), sinapine (271), gramine (272), cepharanthine (273), piperine (274,275), lamellarin D (276), ipobscurine (277), chelerythrine (278), dihydrochelerythrine (279), tryptanthrin (280), and neferine (Figure 6) (281) are some of the other alkaloid agents that exert significant anticancer activity through modulation of VEGF, AP-1, fibroblast growth factor receptor 4 (FGFR4)/ fibroblast growth factor receptor substrate 2a (FRS2a)-ERK1/ 2, NF-kB, Nrf-2/Kelch-like ECH-associated protein 1 (Keap-1), MMP-2, MMP-9, and STAT3.…”

Section: Alkaloidsmentioning

confidence: 99%

Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy

et al. 2022

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BackgroundTumors often progress to a more aggressive phenotype to resist drugs. Multiple dysregulated pathways are behind this tumor behavior which is known as cancer chemoresistance. Thus, there is an emerging need to discover pivotal signaling pathways involved in the resistance to chemotherapeutic agents and cancer immunotherapy. Reports indicate the critical role of the toll-like receptor (TLR)/nuclear factor-κB (NF-κB)/Nod-like receptor pyrin domain-containing (NLRP) pathway in cancer initiation, progression, and development. Therefore, targeting TLR/NF-κB/NLRP signaling is a promising strategy to augment cancer chemotherapy and immunotherapy and to combat chemoresistance. Considering the potential of phytochemicals in the regulation of multiple dysregulated pathways during cancer initiation, promotion, and progression, such compounds could be suitable candidates against cancer chemoresistance.ObjectivesThis is the first comprehensive and systematic review regarding the role of phytochemicals in the mitigation of chemoresistance by regulating the TLR/NF-κB/NLRP signaling pathway in chemotherapy and immunotherapy.MethodsA comprehensive and systematic review was designed based on Web of Science, PubMed, Scopus, and Cochrane electronic databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to include papers on TLR/NF-κB/NLRP and chemotherapy/immunotherapy/chemoresistance by phytochemicals.ResultsPhytochemicals are promising multi-targeting candidates against the TLR/NF-κB/NLRP signaling pathway and interconnected mediators. Employing phenolic compounds, alkaloids, terpenoids, and sulfur compounds could be a promising strategy for managing cancer chemoresistance through the modulation of the TLR/NF-κB/NLRP signaling pathway. Novel delivery systems of phytochemicals in cancer chemotherapy/immunotherapy are also highlighted.ConclusionTargeting TLR/NF-κB/NLRP signaling with bioactive phytocompounds reverses chemoresistance and improves the outcome for chemotherapy and immunotherapy in both preclinical and clinical stages.

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Specific Cytostatic and Cytotoxic Effect of Dihydrochelerythrine in Glioblastoma Cells: Role of NF-κB/β-catenin and STAT3/IL-6 Pathways

Cited by 6 publications

References 0 publications

Reverted effect of mesenchymal stem cells in glioblastoma treated with agathisflavone and its selective antitumoral effect on cell viability, migration, and differentiation via STAT3

Reverted effect of mesenchymal stem cells in glioblastoma treated with agathisflavone and its selective antitumoral effect on cell viability, migration, and differentiation via STAT3

RBPJ contributes to the malignancy of glioblastoma and induction of proneural‐mesenchymal transition via IL‐6‐STAT3 pathway

Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy

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