Anti-osteosarcoma activity of Corynoline via Src/JNK signaling-mediated cell cycle arrest and mitochondrial apoptosis

Corynoline (COR) is an isoquinoline alkaloid derived from the traditional Chinese medicine Corydalis bungeana Turcz, known for its analgesic, antibacterial, neuroprotective, and osteoporosis-alleviating properties. However, its potential molecular effects against osteosarcoma (OS) remain unclear, warranting further investigation. This study demonstrated that COR inhibits OS cell proliferation and promotes apoptosis in a dose-dependent manner. Additionally, COR induced G2/M phase cell cycle arrest. Using an integrative computational and experimental approach, we found the Src/JNK pathway was identified as a significant target. Western blot analysis revealed that OS cells treated with COR showedan increase in levels was evident of p-Src, p-JNK, and p-c-JUN. Moreover, the JNK inhibitor SP600125 counteracted COR's anti-proliferative effects and reversed mitochondrial apoptosis and cell cycle arrest. In vivo, COR significantly reduced tumor size in OS xenograft nude mice without causing toxicity. Following COR treatment, elevated levels of p-JNK and cyclin B1 were observed, while Ki-67 decreased and JNK levels remained unchanged. We finally elucidated the COR inhibits OS via Src/JNK pathway. Given its multifaceted roles in regulating cell behavior in the context of OS, the Src/JNK pathway is being explored for therapeutic interventions. Targeting this pathway could potentially improve treatment outcomes by modulating the balance between cell survival and death in OS. Thus, understanding the Src/JNK pathway is essential for unraveling the intricate mechanisms underlying OS progression and for developing effective therapeutic strategies.