Combination Therapy with Betulinic Acid and TRAIL Increases ROS-Dependent Cytotoxicity and Inhibits PI3K/Akt Signaling in Human Bladder Cancer Cells
10.4062/biomolther.2026.035
- Author:
Cheol PARK
1
;
Hee-Jae CHA
;
Su Hyun HONG
;
Heui-Soo KIM
;
Sun-Hee LEEM
;
Jung-Hyun SHIM
;
Gi-Young KIM
;
Kyoung Ah KANG
;
Jin Won HYUN
;
Yung Hyun CHOI
Author Information
1. Department Division of Basic Sciences, College of Liberal Studies, Dong-eui University, Busan 47340, Republic of Korea
- Publication Type:Original Article
- From:Biomolecules & Therapeutics
2026;34(3):641-651
- CountryRepublic of Korea
- Language:English
-
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively targets cancer cells and induces apoptosis. However, many cancers, including bladder cancer, develop resistance to TRAIL, limiting the efficacy of TRAIL-based therapies. This study investigated whether betulinic acid (BA), a pentacyclic triterpenoid with anticancer and chemosensitizing properties, increases TRAIL-mediated apoptosis in TRAIL-resistant human bladder cancer cells. Combination treatment with BA and TRAIL significantly increased cytotoxicity and apoptosis compared to either treatment alone. This combination treatment also increased reactive oxygen species (ROS) production, increased Bax expression and Bid cleavage (tBid formation), and downregulated Bcl-2 levels. These effects were accompanied by caspase activation via extrinsic and intrinsic pathways, leading to cytochrome c release via mitochondrial membrane destabilization, thereby contributing to increased apoptosis. Furthermore, the combination treatment inhibited phosphoinositide 3-kinase (PI3K) and Akt phosphorylation; this effect was amplified by a PI3K inhibitor but abrogated by ROS inhibition. Collectively, our results suggest that BA sensitizes bladder cancer cells to TRAILinduced apoptosis via ROS-dependent activation of the apoptotic pathway and inhibition of PI3K/Akt signaling. Therefore, the BA and TRAIL combination exhibits potential to overcome TRAIL resistance in human bladder cancer.
