Sesamol Alleviates the Cytotoxic Effect of Cyclophosphamide on Normal Human Lung WI-38 Cells via Suppressing RAGE/NF-κB/Autophagy Signaling

Abstract

Cyclophosphamide (CYL) is a chemotherapeutic medication commonly used in managing various malignancies like breast cancer or leukemia. Though, CYL has been documented to induce lung toxicity. Mechanism of CYL toxicity is through oxidative stress and the release of damage-associated molecular patterns (DAMPs). Sesamol (SES) is a natural antioxidant isolated from Sesamum indicum and its effect against CYL-induced lung toxicity is not studied yet. This study aims to investigate whether SES could prevent any deleterious effects induced by CYL on lung using normal human lung cells, WI-38 cell line, without suppressing its efficacy. Cells were pretreated with SES and/or CYL for 24 h, then cell viability was estimated by MTS and trypan blue assays. The mode of cell death was determined by AO/EB staining. Additionally, caspase-3 level, oxidative stress, and inflammatory markers were evaluated by colorimetric and ELISA techniques. qRT-PCR was performed to evaluate RAGE, NF-κB, and Beclin-1 mRNA-expression. CYL-treated WI-38 cells developed a significantly increased cell death with enhanced oxidative and RAGE/NF-κb/Autophagy signaling, which were all attenuated after pretreatment with SES. Thus, we concluded that SES offered a protective role against CYL-induced lung injury via suppressing oxidative stress and RAGE/NF-κB/Autophagy signaling, which is a natural safe therapeutic option against CYL toxicities. Graphic Abstract

Amentoflavone Mitigates Cyclophosphamide-Induced Pulmonary Toxicity: Involvement of -SIRT-1/Nrf2/Keap1 Axis, JAK-2/STAT-3 Signaling, and Apoptosis

“…Autophagy is an important intracellular process that plays a crucial role in the maintenance of cellular homeostasis and the regulation of cellular differentiation and survival [49]. The affection of the mediators of autophagy was regarded as a possible explanation for the toxic effects of CPA on the lungs [5]. As evidenced in the current study, the autophagic stream was proven to be significantly inhibited in the lung tissues following the administration of CPA.…”

“…The mechanisms of this toxicity may include perturbations of the pro-oxidant/antioxidant balance, augmentation of the inflammatory pathways, and modulation of the apoptotic signals in the pulmonary tissues [4]. Therefore, targeting these potential mechanisms may contribute to the mitigation of the deleterious effects of CPA on the pulmonary tissues [5].…”

RAGE inhibition alleviates lipopolysaccharides-induced lung injury via directly suppressing autophagic apoptosis of type II alveolar epithelial cells

“…Evidence suggests that inhibiting RAGE exerts a therapeutic effect in ARDS animals by restoring alveolar epithelial permeability and pulmonary fluid clearance [ 19 ]. Interestingly, it was reported that RAGE mediates autophagy which participates in the pathogenesis of different lung diseases, including ALI [ 20 ]. A recent study found that the suppression of autophagy improved pulmonary epithelial cell viability and tight junctions [ 21 ].…”