Background:
Lung cancer is one of the most prevalent malignancies and thus the development of novel
therapeutic agents for managing lung cancer is imperative. Tetrandrine, a bis-benzyltetrahydroisoquinoline
alkaloid isolated from Stephania tetrandra S. Moore, has been found to exert cytotoxic effects on cancerous
cells.
Methods:
A series of 5-alkynyltetrandrine derivatives was synthesized via the Sonogashira cross-coupling reactions
and evaluated as potential anti-tumor agents. The anti-tumor activities of 12 compounds on lung cancer
cells (A549) were evaluated using the MTT method. The population of apoptotic cells was measured using a
TUNEL assay. Real-time PCR quantified the gene expression levels of Bcl-2, Bax, survivin and caspase-3. The
content of Cyt-C was detected using a Human Cyt-C ELISA kit.
Results:
Most of these compounds exhibited better activities than tetrandrine itself on A549 cells. Among them,
compound 7 showed the highest cytotoxicity among the tested compounds against human lung adenocarcinoma
A549 cells with an IC50 of 2.94 µM. Preliminary mechanistic studies indicated that compound 7 induced apoptosis
of human lung cancer A549 cells and increased the level of the proapoptotic gene Bax, release of Cyt-C from
mitochondria and activation of caspase-3 genes.
Conclusion:
The results suggest that compound 7 exerts its antitumor activity against A549 cells through the
induction of the intrinsic (mitochondrial) apoptotic pathway. These findings will contribute to the future design
of more effective anti-tumor agents in lung cancer therapy.