Xinyu Wang,Hui Zhang,Ping Bai,Jinjin Shi,Qiaoyun Li,Wei Liu
Inhibition of protein neddylation pathway has emerged an attractive anticancer strategy in pre-clinical studies. MLN4924, as a small molecule inhibitor of the neddylation, has been found to effectively inhibit the growth of a variety of cancer cells. However, its clinical application still faces some major challenges in terms of the poor water solubility, biological stability, poor targeting, and rapid clearance from the body. Herein, we developed a biomimetic nanovesicle platform (named P-PAM/MLN) by ultrasonically storing MLN4924-loaded polyamidoamine (PAMAM) dendrimer into platelet membrane vesicles (PMVs) for tumor therapy. Benefiting from PMVs-based camouflage, P-PAM/MLN exhibited enhanced tumor affinity, avoiding the off-target toxicity of MLN4924. Moreover, P-PAM/MLN could selectively release MLN4924 in response to the acidic microenvironment of lysosomal compartments via "Proton Sponge" effect. Conse-quently, the biomimetic nanovesicles could remarkably inhibit tumor progression with negligible toxicity. In terms of significance, the nanovesicles provide a precisely targeted delivery platform for delivering small molecule drugs to the tumor tissue as well as an effective reference for the combined application of nanocarriers and clinical drugs.
Head and neck squamous carcinoma (HNSCC) is the seventh most common cancer worldwide. Targeted therapeutic drugs for HNSCC are still being explored. Among them, (S)-10-hydroxycamptothecin (10-HCPT), a specific inhibitor of TOP1, functions by DNA double-strand breaks that can inhibit DNA replication and trigger apoptotic cell death subsequently. Previous studies have reported that MLN4924 exerts potent anti-tumor effects by inhibiting cullin–RING ligases and causing substrate accumulation in a variety of cancers. Here, we show that MLN4924 effectively causes dose-dependent accumulation of topoisomerase I (TOP1) and blocks TOP1 ubiquitination. Importantly, neddylation inhibition with MLN4924 acts synergistically with 10-HCPT to suppress cell growth, migration and apoptosis in HNSCC cells. Mechanistically, transcriptome sequencing shows that the cytotoxic effects of the combination of MLN4924 and 10-HCPT may involve activation of the NFKB1 pathway. Taken together, our results suggest that combined treatment with MLN4924 and 10-HCPT may be an effective strategy in HNSCC.
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