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. 2024 Feb 16:12:1352009.
doi: 10.3389/fchem.2024.1352009. eCollection 2024.

Targeting NF-κB signaling cascades of glioblastoma by a natural benzophenone, garcinol, via in vitro and molecular docking approaches

Syed Mohd Danish Rizvi  1 , Ibrahim A Almazni  2 , Mamdoh S Moawadh  3 , Zeyad M Alharbi  3 , Nawal Helmi  4 , Leena S Alqahtani  4 , Talib Hussain  5 , Ahmed Alafnan  5 , Afrasim Moin  1 , AbdElmoneim O Elkhalifa  6 , Amir Mahgoub Awadelkareem  6 , Mohammad Khalid  7 , Rohit Kumar Tiwari  8
Affiliations

Targeting NF-κB signaling cascades of glioblastoma by a natural benzophenone, garcinol, via in vitro and molecular docking approaches

Syed Mohd Danish Rizvi et al. Front Chem. .

Abstract

Glioblastoma multiforme (GBM) is regarded as the most aggressive form of brain tumor delineated by high cellular heterogeneity; it is resistant to conventional therapeutic regimens. In this study, the anti-cancer potential of garcinol, a naturally derived benzophenone, was assessed against GBM. During the analysis, we observed a reduction in the viability of rat glioblastoma C6 cells at a concentration of 30 µM of the extract (p < 0.001). Exposure to garcinol also induced nuclear fragmentation and condensation, as evidenced by DAPI-stained photomicrographs of C6 cells. The dissipation of mitochondrial membrane potential in a dose-dependent fashion was linked to the activation of caspases. Furthermore, it was observed that garcinol mediated the inhibition of NF-κB (p < 0.001) and decreased the expression of genes associated with cell survival (Bcl-XL, Bcl-2, and survivin) and proliferation (cyclin D1). Moreover, garcinol showed interaction with NF-κB through some important amino acid residues, such as Pro275, Trp258, Glu225, and Gly259 during molecular docking analysis. Comparative analysis with positive control (temozolomide) was also performed. We found that garcinol induced apoptotic cell death via inhibiting NF-κB activity in C6 cells, thus implicating it as a plausible therapeutic agent for GBM.

Keywords: NF-κB; anti-cancer; benzophenone; garcinol; glioblastoma multiforme.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Garcinol-induced cytotoxic effects on murine glioblastoma C6 cells expressed as (A) percentage cell viability, (B) IC50 value of garcinol in C6 cells, and (C) garcinol effect on J774A.1 murine alveolar macrophages. **p < 0.01 and ***p < 0.001.
FIGURE 2
FIGURE 2
Efficacy of garcinol in instigating levels of (A) intracellular ROS and (B) quantification of ROS in garcinol-treated C6 cells. *p < 0.05, **p < 0.01, and ***p < 0.001.
FIGURE 3
FIGURE 3
Garcinol-mediated effects on condensation of chromatin in C6 cells post-24 h exposure. Scale bar = 100 μm.
FIGURE 4
FIGURE 4
Garcinol-mediated effects dissipation of ΔΨm in C6 cells in a dose-dependent manner. Scale bar = 100 μm.
FIGURE 5
FIGURE 5
Activity levels of different caspases post-treatment with garcinol in C6 cells. *p < 0.05, **p < 0.01, and ***p < 0.001.
FIGURE 6
FIGURE 6
Expression levels of NF-κB along with various key genes involved in regulating the apoptotic cell death within C6 cells exposed to garcinol.
FIGURE 7
FIGURE 7
Quantification of NF-κB along with various key genes involved in regulating the apoptotic cell death expressed within C6 cells exposed to garcinol. *p < 0.05, **p < 0.01, and ***p < 0.001.
FIGURE 8
FIGURE 8
Levels of NF-κB in murine glioblastoma C6 cells treated with varying garcinol concentrations for 24 h. *p < 0.05, **p < 0.01, and ***p < 0.001.
FIGURE 9
FIGURE 9
qRT-PCR observation indicating the expression of key apoptosis-controlling genes in murine glioblastoma C6 cells treated with varying concentration of garcinol. *p < 0.05, **p < 0.01, and ***p < 0.001.
FIGURE 10
FIGURE 10
3D structure of the docked complex of NF-κB and garcinol.
FIGURE 11
FIGURE 11
3D structure of the docked complex of NF-κB and temozolomide.
See this image and copyright information in PMC

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