The Modulation of Cell Plasticity by Budesonide: Beyond the Metabolic and Anti-Inflammatory Actions of Glucocorticoids

Abstract

The synthetic cortisol analog budesonide (BUD) is an essential drug employed to manage chronic inflammatory diseases in humans, mainly those involving gastroenteric and airway mucosa, such as rhinitis, laryngitis, bronchitis, esophagitis, gastritis, and colitis, with high levels of success. As a glucocorticoid, BUD prevents the expression of pro-inflammatory cytokines/chemokines and the recruitment of immune cells into the inflamed mucosa. However, emerging evidence indicates that BUD, unlike classical glucocorticoids, is also a potent modulator of stem and cancer cell behavior/plasticity. Certainly, BUD stabilizes cell-cell adhesions, preventing embryonic stem cell differentiation and inhibiting the development of 3D gastruloids. In addition, BUD inhibits the motile/invasive propensity of different cancer cells, including breast, lung, and pancreatic cancer. Finally, it prevents the infection of positive single-stranded human-infecting RNA viruses such as SARS-CoV-2. At a molecular level, BUD induces epigenetic changes and modifies the transcriptome of epithelial, stem, and cancer cells, providing molecular support to the immune cell-independent activity of BUD. Here, we performed an in-depth review of these unexpected activities of BUD, identified by unbiased drug screening programs, and we emphasize the molecular mechanisms modulated by this efficacious drug that deserve further research.

Keywords: SARS-CoV-2; budesonide; cancer cells; gastruloids; metastasis; stem cells.

Figure 1

Schematic showing the chemical structure of the synthetic corticosteroid BUD, diseases treated with BUD, and vehicles for delivery. The residues shared by BUD, hydrocortisone, and classical corticosteroids are indicated by light blue circles, whereas the specific/atypical structural features of BUD are shown in red. The chronic IDs that affect the gastroenteric and airway mucosa and are usually treated with BUD are presented on top. Innovative BUD delivery vehicles are shown at the bottom. In the chemical structure of cyclodextrin, R = 2-hydroxypropyl or H.

Figure 2

Schematic representation of the re-epithelialization actions of BUD in gastroenteric inflammatory diseases. The diagram is representative of eosinophilic esophagitis, but similar effects of BUD are described in ulcerative and microscopic colitis. The loss of cell–cell adhesive interactions reduces epithelial barrier activity and allows for the penetration of allergens, chemicals, and/or microorganisms, which is followed by the infiltration of immune cells and, eventually, inflammation. BUD suppresses mucosa inflammation by promoting cell–cell adhesion and inhibiting immune cell transmigration.

Figure 3

Schematic representation of the inhibitory effect of BUD on stem and cancer cell plasticity. A phenotype-based HTS reveals that BUD, unlike the 24 other examined GCs, is a potent modulator of the cell colony morphology in ESCs (upper images). With regard to the specific mechanisms, BUD appears to play a role in maintaining cell–cell adhesive interactions by inducing the generation of highly compacted cell colonies (upper right diagrams). In addition, BUD inhibits the migration of SUIM-159 breast cancer cells favoring cell–cell adhesions (bottom left images). Similar results are obtained by assaying A549 lung cancer cells. Moreover, in an in vitro mouse model of breast cancer, BUD is found to reduce lung metastasis from primary mammary tumors (bottom right images).

Figure 4

Schematic depicting the role of BUD in the maintenance of high levels of the adhesive protein E-cadherin at the cell–cell interface. Spontaneous gastruloid development and proline-induced embryonic-stem-to-mesenchymal transition (esMT) are depicted in the upper diagrams. A similar role of BUD involving its effect on E-cadherin expression has been described in chronic IDs involving the gastroenteric and airway mucosa. The diagram at the bottom depicts E-cadherin-mediated cell junction stabilization based on the inhibition of its intercellular-to-intracellular delocalization (reshuffling).

Figure 5

Schematic depicting the impact of BUD on the epigenetic landscape of stem and cancer cells. BUD decreases DNA and histone methylation levels and induces mesenchymal-to-epithelial transition. The model presented at the bottom depicts the compartmentalization of two metabolites, ascorbic acid (VitC) and alpha-ketoglutarate (αKG), which are essential co-factors/substrates for the activity of dioxygenase enzymes involved in collagen hydroxylation (as prolyl 4-hydroxylase subunit alpha 2/P4HA2) in the cytoplasm (endoplasmic reticulum/ER) and in DNA and histone hydroxylation/demethylation (as ten-eleven translocation/TET and Jumonji/JMJ enzymes) in the nucleus. As proposed in D’Aniello et al. [96], when collagen synthesis is inhibited in the ER, the availability of VitC and αKG increases in the nucleus, thus favoring the activity of nuclear DNA and histone demethylases.

Figure 6

Schematic showing the inhibitory effect of BUD on the infection/replication of (+)RNA viruses. The membrane receptors of each virus are indicated in the upper part of the diagram. BUD inhibits the infection/replication of these viruses by reducing the expression of their receptors (angiotensin-converting enzyme-2/ACE2 for SARS-CoV2 and intercellular adhesion molecule 1/ICAM-1 for HRV) or interfering with the trafficking/fluidity of the membrane complexes that are necessary for the endocytosis (endosome) and/or the replication (double membrane vesicles) of the virus.