Assessment of the Anti-invasion Potential and Mechanism of Select Cinnamic Acid Derivatives on Human Lung Adenocarcinoma Cells

Patients with lung adenocarcinoma are often diagnosed with metastasizing symptoms and die of early and distal metastasis. Metastasis is made up of a cascade of interrelated and sequential steps, including cell adhesion, extracellular matrix degradation, cell movement, and invasion. Hence, substances carrying the ability to stop one of the metastasis-associated steps could be a potential candidate for preventing tumor cells from metastasizing and prolonging the life of cancer patients. Cinnamic acid (CA) was demonstrated to be such a candidate for human lung adenocarcinoma cells. Nevertheless, the effectiveness of CA derivatives on invasion of lung cancer cells is still unclear. The aims of this study were to explore the mechanisms underlying several select CA derivatives against invasion of human lung adenocarcinoma A549 cells. The results revealed that caffeic acid (CAA), chlorogenic acid (CHA), and ferulic acid (FA) can inhibit phorbol-12-myristate-13-acetate (PMA)-stimulated invasion of A549 cells at a concentration of ≥100 μM. The MMP-9 activity was suppressed by these compounds through regulating urokinase-type plasminogen activator (uPA), tissue inhibitor of metalloproteinase (TIMP)-1, plasminogen activator inhibitor (PAI)-1, and PAI-2; the cell-matrix adhesion was decreased by CAA only. The proposed molecular mechanism involved not only decreasing the signaling of MAPK and PI3K/Akt but also inactivating NF-κB, AP-1, and STAT3. In the present study, we selected CAA, CHA, and FA as potential inhibitors for invasive behaviors of human lung adenocarcinoma cells and disclosed the possible mechanisms. The association between structural features and anti-invasive activity of these compounds cannot be determined here and needs to be further verified

Sulforaphane Potentiates the Efficacy of Imatinib against Chronic Leukemia Cancer Stem Cells through Enhanced Abrogation of Wnt/β-Catenin Function

Sulforaphane (SFN) has been indicated for the prevention and suppression of tumorigenesis in solid tumors. Herein, we evaluated SFN’s effects on imatinib (IM)-resistant leukemia stem cells (LSCs). CD34⁺/CD38^– and CD34⁺/CD38⁺ LSCs were isolated from KU812 cell line flowcytometrically. Isolated LSCs showed high expression of <i>Oct4</i>, <i>CD133</i>, <i>β-catenin</i>, and <i>Sox2</i> and IM resistance. Differentially, CD34⁺/CD38^– LSCs demonstrated higher BCR-ABL and β-catenin expression and imatinib (IM) resistance than CD34⁺/CD38⁺ counterparts. IM and SFN combined treatment sensitized CD34⁺/CD38^– LSCs and induced apoptosis, shown by increased caspase 3, PARP, and Bax while decreased Bcl-2 expression. Additionally, the combined treatment reduced BCR-ABL and β-catenin and MDR-1 protein expression. Mechanistically, IM and SFN combined treatment resensitized LSCs by inducing intracellular reactive oxygen species (ROS). Importantly, β-catenin-silenced LSCs exhibited reduced glutathione <i>S</i>-transferase pi 1 (GSTP1) expression and intracellular GSH level, which led to increased sensitivity toward IM and SFN. We demonstrated that IM and SFN combined treatment effectively eliminated CD34⁺/CD38^– LSCs. Since SFN has been shown well tolerated in both animals and human, this regimen could be considered for clinical trials