Targeting breast cancer cell signaling molecules PI3K and Akt by phytochemicals Cannabidiol, Nimbin and Acetogenin: An <i>in silico</i> approach

Mittal, R.; Chaudhry, Narender; Mukherjee, Tapan Kumar

doi:10.7150/jbm.25815

Cited by 9 publications

(7 citation statements)

References 7 publications

(7 reference statements)

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“…The PI3K/AKT pathway plays a predominant role in cell proliferation, survival, and progression [26]. It is known that both AKT and PI3K have several active binding sites specific for CBD [27]. However, it is not clear how the CBD-kinase adduct formation affects the enzymatic activity of these proteins.…”

Section: Discussionmentioning

confidence: 99%

The Differences in the Proteome Profile of Cannabidiol-Treated Skin Fibroblasts following UVA or UVB Irradiation in 2D and 3D Cell Cultures

Gęgotek

Atalay

Domingues

et al. 2019

Cells

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Cannabidiol (CBD), as the only phytocannabinoid that has no psychoactive effect, has both antioxidant and anti-inflammatory effects, and thus might be suggested as a cytoprotective compound against UV-induced metabolic changes in skin cells. Therefore, the aim of this study was to investigate the level of protective CBD activity by evaluating the proteomic profile of 2D and 3D cultured skin fibroblasts models following exposure to UVA and UVB radiation. The CBD cytoprotective effect against UV-induced damage in 2D and 3D cultured fibroblasts were different. The main alterations focus on the range of cell reaction and involved different proteins associated with various molecular functions. In the 2D cultured cells, following UV radiation, the major changes were associated with proteins involved in antioxidant response and inflammation, while, in the 3D cultured fibroblasts, CBD action against UV induced changes were mainly associated with the activation of signalling pathways. Therefore, the knowledge of the CBD action in a multilayer skin cells model allowed for the prediction of changes in cell-cell interactions and skin cell metabolism. Knowledge about the lower protective effect of CBD in 3D cultured fibroblasts should be taken into account during the design of UV light protection.

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Section: Discussionmentioning

confidence: 99%

The Differences in the Proteome Profile of Cannabidiol-Treated Skin Fibroblasts following UVA or UVB Irradiation in 2D and 3D Cell Cultures

Gęgotek

Atalay

Domingues

et al. 2019

Cells

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“…Hence, these compounds possibly will perform the role as an inhibitor to AKT1 and conferring anticancer property to the plant CA. Mittal et al [10] evaluated that the breast cancer cell signalling molecule Akt forms the binding site for cannabidiol, a natural compound with potential anticancer drug consists of GLU191, HIS194 and ASP274 residues at the binding site. The study compiled by Kumar et al [36] demonstrated that the PDB‐derived AKT1 protein (PDB ID 4EJN) was subjected to molecular docking analysis using AutoDock software with 14 different native inhibitors of AKT1 derived from Selleck Chemicals website.…”

Section: Resultsmentioning

confidence: 99%

“…From these findings, Akt is observed to be an attractive target to overcome the issue of lung cancer [10]. Therefore, the inhibition of Akt by plant-derived molecules is of immense therapeutic significance for the development of anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

“…During the localisation event at the plasma membrane, the Akt gets phosphorylated, which induces protein synthesis and growth of cells through the activation of mammalian target of rapamycin. From these findings, Akt is observed to be an attractive target to overcome the issue of lung cancer [10]. Therefore, the inhibition of Akt by plant‐derived molecules is of immense therapeutic significance for the development of anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

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In silicoandinvitroapproaches to evaluate the bioactivity of Cassia auriculata L extracts

Anitha¹,

Rajakannu²,

Kumar³

2020

IET nanobiotechnol.

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The present study is an attempt to evaluate the in vitro anti-inflammatory and in silico anticancer potentials of the plant Cassia auriculata (CA). The aerial parts of CA were subjected to solvent extraction, and the extracts were fractionised by gas chromatography and mass spectrometry analysis for its phytochemical content. The antiinflammatory activity of the extracts were confirmed by the IC 50 value of 125.02 µg/ml for red blood cell membrane stabilisation and 195.7 µg/ml for inhibition of protein denaturation activity. The interaction of bioactive compounds of CA ethanol extract with target protein was predicted through molecular docking studies, serine/threonine-protein kinase B (AKT1), responsible for development and progression of lung cancer using AutoDock tools. Extensive studies have been carried out on a range of kinase inhibitors targeting Akt, but obtaining promising results is a challenge yet due to its toxicity and resistance issues. Yohimbine, undecanoic acid 10-methylethyl ester and chrysin significantly bind to the target protein with least binding energy. Hence, the present paper establishes the anti-inflammatory and anticancer capacities of CA ethanol extract as an alternative to the existing therapeutic approach to inflammation and cancer through a systematic in vitro and in silico approaches supplementing the findings.

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“…When wortmannin, a specific inhibitor of AKT phosphorylation, was added to the 6D cells, these showed reduced migration to levels similar to those in cells treated with CBD. It was very recently shown in an in silico study that CBD binds to the active site of PI3K and AKT [26]. As a consequence of AKT inactivation by CBD, a crucial point for crosstalk in the IL-1β-and CBD-induced pathways, 6D cells could undergo reversion to an epithelial phenotype.…”

Section: Discussionmentioning

confidence: 99%

CBD Reverts the Mesenchymal Invasive Phenotype of Breast Cancer Cells Induced by the Inflammatory Cytokine IL-1β

García-Morales

Castillo

Tapia-Ramı́rez

et al. 2020

IJMS

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Cannabidiol (CBD) has been used to treat a variety of cancers and inflammatory conditions with controversial results. In previous work, we have shown that breast cancer MCF-7 cells, selected by their response to inflammatory IL-1β cytokine, acquire a malignant phenotype (6D cells) through an epithelial–mesenchymal transition (EMT). We evaluated CBD as a potential inhibitor of this transition and inducer of reversion to a non-invasive phenotype. It decreased 6D cell viability, downregulating expression of receptor CB1. The CBD blocked migration and progression of the IL-1β-induced signaling pathway IL-1β/IL-1RI/β-catenin, the driver of EMT. Cannabidiol reestablished the epithelial organization lost by dispersion of the cells and re-localized E-cadherin and β-catenin at the adherens junctions. It also prevented β-catenin nuclear translocation and decreased over-expression of genes for ∆Np63α, BIRC3, and ID1 proteins, induced by IL-1β for acquisition of malignant features. Cannabidiol inhibited the protein kinase B (AKT) activation, a crucial effector in the IL-1β/IL-1RI/β-catenin pathway, indicating that at this point there is crosstalk between IL-1β and CBD signaling which results in phenotype reversion. Our 6D cell system allowed step-by-step analysis of the phenotype transition and better understanding of mechanisms by which CBD blocks and reverts the effects of inflammatory IL-1β in the EMT.

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Targeting breast cancer cell signaling molecules PI3K and Akt by phytochemicals Cannabidiol, Nimbin and Acetogenin: An in silico approach

Cited by 9 publications

References 7 publications

The Differences in the Proteome Profile of Cannabidiol-Treated Skin Fibroblasts following UVA or UVB Irradiation in 2D and 3D Cell Cultures

The Differences in the Proteome Profile of Cannabidiol-Treated Skin Fibroblasts following UVA or UVB Irradiation in 2D and 3D Cell Cultures

In silicoandinvitroapproaches to evaluate the bioactivity of Cassia auriculata L extracts

CBD Reverts the Mesenchymal Invasive Phenotype of Breast Cancer Cells Induced by the Inflammatory Cytokine IL-1β

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