New triazole-chalcone hybrids as potent apoptosis inducers through caspase activation in A549 human lung adenocarcinoma cells

抄録

Background: Triazoles and chalcones are well known biologically active pharmacophores which have captured considerable research interest. The development of hybrid molecules through the combination of different pharmacophores may lead to compounds with interesting biological profiles. In our continued research to develop potential chemotherapeutic agents we designed and synthesized a library of triazole and chalcone hybrids. Our expectation was that their synergistic effect may overcome the growing problem of cancer resistance.

Materials and methods: Forty allyl and phenyl triazole-chalcone hybrids were designed, synthesized and evaluated for their cytotoxicities against human cancer cells by sulforhodamine B (SRB) and Bromodeoxyuridine (5-bromo-2-deoxyuridine, BrdU) incorporation assays. Apoptosis analysis was carried out by flow cytometry. To elucidate antitumor mechanisms of the potent compounds, expression and activation status of cell apoptosis regulators were thoroughly analyzed by immunoblotting.

Results: The SRB assay experienced promising cytotoxic activity against different cancer cell lines. Independently BrdU incorporation assay showed that derivatives containing allyl triazole is more active than that containing phenyl triazole against human lung adenocarcinoma A549 cells. Furthermore, among all synthesized hybrids studied, the compounds 26, 27, 29, 43 and 49 have shown the highest cytotoxicity against A549 cells (IC₅₀= 6.06, 4.4, 7.55, 16.04 and 8.04 µM, respectively) compared to cisplatin as a positive control (IC₅₀= 15.3 µM). Flow cytometric analysis for these compounds showed increase number of apoptotic cells in a dose-dependent manner. Further mechanistic study demonstrated that triazole-chalcone hybrids induced apoptosis via increased level of proapoptotic protein Bax, release of cytochrome c from mitochondria and activation of caspase-3/8/9 proteins. In addition, general caspase inhibition by pan-caspase inhibitor, z-VAD-fmk, significantly decreased the apoptosis induced by triazole-chalcone hybrids, suggesting dependency on caspase-3 pathway to increase apoptosis.

Conclusion: The overall performance of triazole-chalcone hybrids led us to believe that these compounds might be potential candidates for anticancer drugs development.

Keywords: Triazole-chalcone hybrids, apoptosis, caspase activation