A nitric oxide donating β-elemene derivative induces reactive oxygen species associated apoptosis and reduces STAT3 phosphorylation in medulloblastoma cells

Medulloblastoma (MB) is a highly aggressive pediatric brain tumor associated with aberrant activation of pro-survival signaling proteins, including Src, JAK2, STAT3, and PI3K/Akt. Here, we developed D1, a novel nitric oxide (NO)-donating β-elemene derivative, and investigated its antitumor activity and associated molecular changes in MB. D1 exhibited markedly enhanced antiproliferative activity compared with β-elemene, achieving nanomolar IC50 values in MB cell lines. Functionally, D1 significantly inhibited cell proliferation and induced apoptosis in a dose-dependent manner. D1 also triggered intracellular reactive oxygen species (ROS) accumulation, and ROS scavenging with N-acetyl-L-cysteine (NAC) attenuated D1-induced growth inhibition and apoptosis, indicating that ROS contributes to these effects. At the molecular level, D1 reduced phosphorylation of Src, JAK2, STAT3, PI3K, and Akt. These signaling changes were accompanied by increased Bax and cleaved caspase-3 and decreased Bcl-2 expression. NAC partially reversed the changes in protein phosphorylation, apoptotic markers, and cell viability, supporting a shared ROS-dependent component without establishing a linear relationship among the affected signaling proteins. In vivo, D1 significantly reduced tumor growth in MB xenograft models without evident body-weight loss, decreased Ki67 expression by immunohistochemistry, and reduced p-Akt and p-STAT3 expression in tumor lysates. Collectively, D1 displays antitumor activity accompanied by ROS-dependent suppression of Src, JAK2, STAT3, and PI3K/Akt signaling and activation of apoptosis.