Abstract
CONTEXT: Ursolic acid (UA), a natural product, shows a broad spectrum of anticancer effects. However, the poor bioavailability and efficacy of UA limit its clinical application. OBJECTIVE: We developed novel analogues of UA with enhanced antitumor activities by the extensive chemical modification of UA. MATERIALS AND METHODS: We developed multiple compounds by structural modification of UA, and found that UA232 had stronger activity than UA. The effects of UA232 (0-50 μM) on inhibiting the proliferation of A549 and H460 cells were determined by CCK-8 for 24, 48, or 72 h. The proapoptotic effect of UA232 was analyzed by microscopy and flow cytometry, and the potential signal pathway affected by UA232 was further validated by Western blotting and flow cytometry. RESULTS: Compared with UA, UA232 showed a stronger ability to inhibit the proliferation of lung cancer cells (IC(50) = 5.4-6.1 μM for A549 and 3.9-5.7 μM for H460 cells). UA232 could induce not only cell cycle arrest in the G0/G1 phase but also apoptosis in both A549 and H460 cells. The treatment of UA232 could lead to an increase of CHOP expression rather than an increase in Bax or caspase-8, indicating that the apoptosis induced by UA232 was correlated with the endoplasmic reticulum stress (ER stress) pathway. Treatment with the ER stress-specific inhibitor, 4-PBA, decreased the ability of UA232 to induce apoptosis in A549 and H460 cells. CONCLUSION: UA232 induced apoptosis through the ER stress pathway, and showed stronger growth-inhibitory effects in A549 and H460 cells compared to UA, which may be a potential anticancer drug to suppress the proliferation of lung cancer.