Bufadienolides as bioorganic anticancer agents: Mechanistic insights into apoptosis, cell cycle arrest and signal pathway modulation.

Bufadienolides, a group of C-24 steroidal compounds found in toad venom and certain plants, have emerged as promising candidates for anticancer drug development due to their broad-spectrum cytotoxicity and multitargeted molecular mechanisms. These compounds demonstrate a range of biological effects, including the induction of apoptosis and autophagy, inhibition of metastasis and angiogenesis, and modulation of the tumor immune microenvironment. Mechanistically, bufadienolides influence critical signaling cascades such as PI3K/Akt, MAPK, and NF-κB, and also affect cell cycle regulation and mitochondrial dynamics. Despite extensive in vitro and in vivo evidence supporting their antitumor potential across various cancer types, including hepatocellular carcinoma, breast, lung, and colon cancers, their clinical translation remains limited. Major challenges include poor solubility, low oral bioavailability, and cardiotoxicity, which restrict therapeutic use. Advances in drug delivery systems - such as nanocarriers, liposomes, and prodrug strategies - have shown promise in improving pharmacokinetic profiles and enhancing selective tumor targeting. The review also summarizes recent clinical studies involving Huachansu, a traditional preparation rich in bufadienolides, which indicate potential benefits in quality of life and disease stabilization but fall short of demonstrating significant survival benefits. Continued efforts are required to refine delivery platforms, reduce systemic toxicity, and validate efficacy in well-controlled clinical trials. Collectively, current evidence supports the rationale for further exploration of bufadienolides as novel anticancer agents with multimodal mechanisms.