Silibinin Regulates Tumor Progression and Tumorsphere Formation by Suppressing PD-L1 Expression in Non-Small Cell Lung Cancer (NSCLC) Cells

Abstract

Recently, natural compounds have been used globally for cancer treatment studies. Silibinin is a natural compound extracted from Silybum marianum (milk thistle), which has been suggested as an anticancer drug through various studies. Studies on its activity in various cancers are undergoing. This study demonstrated the molecular signaling behind the anticancer activity of silibinin in non-small cell lung cancer (NSCLC). Quantitative real-time polymerase chain reaction and Western blotting analysis were performed for molecular signaling analysis. Wound healing assay, invasion assay, and in vitro angiogenesis were performed for the anticancer activity of silibinin. The results indicated that silibinin inhibited A549, H292, and H460 cell proliferation in a concentration-dependent manner, as confirmed by the induction of G0/G1 cell cycle arrest and apoptosis and the inhibition of tumor angiogenesis, migration, and invasion. This study also assessed the role of silibinin in suppressing tumorsphere formation using the tumorsphere formation assay. By binding to the epidermal growth factor receptor (EGFR), silibinin downregulated phosphorylated EGFR expression, which then inhibited its downstream targets, the JAK2/STAT5 and PI3K/AKT pathways, and thereby reduced matrix metalloproteinase, PD-L1, and vascular endothelial growth factor expression. Binding analysis demonstrated that STAT5 binds to the PD-L1 promoter region in the nucleus and silibinin inhibited the STAT5/PD-L1 complex. Altogether, silibinin could be considered as a candidate for tumor immunotherapy and cancer stem cell-targeted therapy.

Antitumor Effects of Natural Bioactive Ursolic Acid in Embryonic Cancer Stem Cells

“…Previous studies have demonstrated that UA can induce cell cycle arrest and apoptosis in several cancer types [ 31 – 33 ]. ROS generation tremendously plays an important role in the anticancer activity of a natural compound [ 34 ]. We found that UA treatment elevated the expression of iNOS at the transcriptional and translational levels so that iNOS induction leads to ROS generation [ 7 ].…”

Iron Metabolism as a Potential Mechanism for Inducing TRAIL-Mediated Extrinsic Apoptosis Using Methylsulfonylmethane in Embryonic Cancer Stem Cells

“…Previous studies have shown that MSM can induce mitochondrial apoptosis against various cancer types [ 31 , 32 ]. ROS generation plays a vital role in the anticancer activity of a natural compound [ 39 ]. We found that MSM elevated the expression of iNOS at the transcriptional and translational levels so that iNOS induction leads to ROS generation [ 24 ].…”

Application Potential of Plant-Derived Medicines in Prevention and Treatment of Platinum-Induced Peripheral Neurotoxicity

“…In the study, Silibinin, as the antioxidant compound, characterizes oxidative stress parameters in a rat model of oxaliplatin-induced neuropathy. Additionally, the hepatoprotective effects ( Loguercio and Festi, 2011 ) as well as the anticancer activity ( Rugamba et al, 2021 ; Zhou et al, 2021 )cooperatively impart silibinin a ubiquitous profile that distinguishes the compound from other antioxidant agents used clinically for the treatment of oxaliplatin-induced neuropathy.…”