A series of mono- and di-methylenecyclohexenone derivatives, 3a – f and 4a – f , respectively, were designed and synthesized from piperlongumine (PL) and their in vitro and in vivo pharmacological properties were evaluated. A majority of the compounds exhibited a potent antiproliferative effect on five human cancer cell lines, especially those causing breast cancer. Compound 4f showed the highest antiproliferative potency among all of the compounds, almost a 10-fold higher inhibitory potency against thioredoxin reductase (TrxR) compared with PL in cells causing breast cancer. In addition, 4f was found to increase the levels of reactive oxygen species (ROS), thus leading to more potent antiproliferative effects. More importantly, the suppression assays of migration and invasion revealed that compound 4f could reverse the epithelial–mesenchymal transition induced by the transforming growth factor β1, and exhibit prominent anti-metastasis effects. Compound 4f also showed strong inhibition potency toward solid tumors of breast cancer in vivo . Our findings show that compound 4f is a promising therapeutic candidate in the treatment of breast cancer, which, however, needs further research to be proved.
Thioredoxin reductase (TrxR) is an essential mammalian enzyme that possesses a selenocysteine active site. TrxR is overexpressed in many malignant tumors and has a close relationship with apoptosis, drug resistance, recurrence and metastasis of tumors. Recently, TrxR has emerged as a promising target for anticancer therapy. Herein, we developed a TrxR-interfering drug delivery system (DDS) based on RGD-PEG-PUSeSe-PEG-RGD self-assembling micelles for imaging-guided gemcitabine (GEM) chemosensitization and anti-recurrence/metastasis therapy. The diselenide-containing micelles were degraded in response to TrxR stimuli for GEM releasing. In the meantime, the dissociated polymers’ chain segments targeted the active site of TrxR via Se–Se/Se–S dynamic reactions for activity inhibition. This inhibition by the micelles not only provided chemosensitization, but reduced tumor recurrence/metastasis risk via the induction of residual tumor cell apoptosis by triggering ROS production post-chemotherapy. In this work, we took the transformation between Se-containing dynamic covalent bonds developed by our group from in vitro to in vivo , which furthered the knowledge on the biochemistry of selenium and provided aspects to develop new TrxR inhibitors. Overall, the TrxR-interfering DDS combined excellent antitumor effects for primary solid tumors with the inhibition of tumor recurrence/metastasis during post-treatment care, providing new perspectives for efficient cancer therapy.
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