Boosting synergism of chemo- and immuno-therapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

Effects of Bortezomib on proliferation, cell cycle and activation of NF-?B of non-small cell lung cancer cells / 解放军医学杂志

Objective To study the effect of Bortezomib on proliferation, apoptosis, cell cycles and activation of NF-?B of non-small cell lung cancer cells (NSCLC) in vitro. Methods The inhibitory action of Bortezomib on cellular growth was determined by MTT. The effects of Bortezomib on cell cycle and apoptosis were assessed by flow cytometry. The influence of Bortezomib on the expressions of NF-?B, I?B and Bcl-2 were detected with Western blotting. Results The inhibitory effects of Bortezomib on the proliferation of NSCLC cells showed a time-and concentration-dependent manner. The growth of NSCLC cells was arrested at G2/M stage after treatment with Bortesomib at 25nmol/L for 48h. Basal expression of NF-?B was found to exist in all the 6 cell lines, with NF-?B expression in nucleus showing an inverse correlation with I?B expression in cytoplasm. Bortezomib threw no significant influence on the basal expression of NF-?B, but significantly blocked the TNF-?-induced nuclear translocation of NF-?B and down-regulated the expression of anti-apoptosis protein Bcl-2 in a time-and concentration-dependent manner. Conclusion With NF-?B-dependent pathway, Bortezomib may inhibit the proliferation of NSCLC cells and induce apoptosis.