1,2,3-Triazole tethered 1,2,4‑trioxane trimer induces apoptosis in metastatic cancer cells and inhibits their proliferation, migration and invasion

Abstract

Artemisinin (ART) has been in use against different cancer cells and its derivatives and conjugates are more cytotoxic to iron-rich cancer cells. It is desirable to develop easily achievable synthetic 1,2,4-trioxanes having the same pharmacophore as that of ART. To explore more efficient compounds, a 1,2,3-triazole tethered 1,2,4‑trioxane trimer (4T) was synthesized and the anti-cancer effects of ART and 4T on MDA-MB-435 and MDA-MB-231 cells were investigated concerning regulation of osteopontin (OPN) expression, which is associated with cancer progression and malignancy. 1H NMR and 13C NMR, oxidative stress analysis, flow cytometry, western blot, Real-Time PCR, transfections, luciferase assay, cell viability, proliferation, migration and chemotactic invasion assays were used in this study. It was observed that the 4T induced apoptosis by inhibiting Bcl-2 (~0.6-fold) and cleavage of caspase-3 (intrinsic pathway) in these metastatic cancer cells, and also reduced colony formation, migration and invasion of these cancer cells. The treatment of 4T decreased the reduced glutathione level and increased the activities of glucose-6-phosphate dehydrogenase and glutathione reductase in the 4T treated cancer cells as compared to their respective controls. Further, the expression of OPN was diminished (~0.5-fold) by the 4T in these cell lines. It was also observed that the key mitogen-activated protein kinase pathway proteins, mitogen-activated protein kinase kinase1/2 (~1.8-fold) and extracellular signal-regulated kinase1/2 (~16-fold), were also activated following the treatment of the 4T. However, the phosphorylated c-Jun level, a component of activator protein-1, was significantly reduced in these cancer cells upon 4T treatment. Taken together, we hypothesize that 4T may be useful for controlling cancer progression and malignancy.