ABSTRACT
[This corrects the article DOI: 10.7150/thno.46467.].
ABSTRACT
Rationale: Malignant ascites caused by cancer cells results in poor prognosis and short average survival time. No effective treatment is currently available for malignant ascites. In this study, the effects of lentinan (LNT)-functionalized selenium nanoparticles (Selene) on malignant ascites were evaluated. Furthermore, the mechanism of Selene targeting mitochondria of tumor cells were also investigated. Methods: Selene were synthesized and characterized by TEM, AFM and particle size analysis. The OVCAR-3 and EAC cells induced ascites models were used to evaluate the effects of Selene on malignant ascites. Proteomic analysis, immunofluorescence, TEM and ICP-MS were used to determine the location of Selene in tumor cells. Mitochondrial membrane potential, ROS, ATP content, and caspase-1/3 activity were detected to evaluate the effect of Selene on mitochondrial function and cell apoptosis. Immunofluorescence, Co-IP, pull-down, duolink, Western blot, and FPLC were used to investigate the pathway of Selene targeting mitochondria. Results: Selene could effectively inhibit ascites induced by OVCAR-3 and EAC cells. Selene was mainly located in the mitochondria of tumor cells and induced apoptosis of tumor cells. The LNT in Selene was involved in caveolae-mediated endocytosis through the interaction between toll-like receptor-4 (TLR4) and caveolin 1 (CAV1). Furthermore, the Selene in the endocytic vesicles could enter the mitochondria via the mitochondrial membrane fusion pathway, which was mediated by TLR4/TNF receptor associated factor 3 (TRAF3)/mitofusin-1 (MFN1) protein complex. Conclusion: Selene is a candidate anticancer drug for the treatment of malignant ascites. And TLR4/TRAF3/MFN1 may be a specific nano-drug delivery pathway that could target the mitochondria.
Subject(s)
GTP Phosphohydrolases/metabolism , Lentinan/pharmacology , Mitochondria/drug effects , Mitochondrial Membrane Transport Proteins/metabolism , Nanoparticles/chemistry , Selenium/pharmacology , TNF Receptor-Associated Factor 3/metabolism , Toll-Like Receptor 4/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Caveolae/drug effects , Caveolae/metabolism , Cell Line, Tumor , Endocytosis/drug effects , Female , Humans , Lentinan/chemistry , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred BALB C , Mitochondria/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Proteomics/methods , Reactive Oxygen Species/metabolism , Selenium/chemistry , Signal Transduction/drug effectsABSTRACT
BACKGROUND: Hypoxia commonly occurs in solid tumors. The hypoxia in the center of solid tumors considerably decreases the chemosensitivity of tumor cells and induces epithelial-mesenchymal transition (EMT) as well as drug resistance of antitumor drugs. METHODS: Here, the effects of salidroside (Sal) combined with platinum drugs on human hepatocellular carcinoma were examined in vitro and in vivo. We investigated the antitumor effects of Sal by inhibiting the drug resistance and explained its mechanism in inhibiting tumor growth. FINDINGS: The results showed that Sal co-administration reverses the drug resistance of platinum drugs and suppressed metastasis induced by the hypoxic tumor microenvironment. Sal promoted the degradation of HIF-1α. In conclusion, Sal significantly increased the sensitivity to platinum drugs and inhibited hypoxia-induced EMT in hepatocellular carcinoma (HCC) through inhibiting HIF-1α signaling pathway. INTERPRETATION: Therefore, Sal may be an effective platinum drug sensitizer that can improve the chemotherapeutic efficacy in patients with HCC.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/drug effects , Glucosides/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia/metabolism , Phenols/pharmacology , Signal Transduction/drug effects , Tumor Microenvironment/drug effects , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Computational Biology/methods , Disease Models, Animal , Epithelial-Mesenchymal Transition/drug effects , Gene Expression Profiling , Glucosides/chemistry , Humans , Hypoxia/genetics , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Mice , Phenols/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Artemisinin and its derivatives exhibit a high activity against a range of cancer cell types both in vitro and in vivo. In clinical practice, platinum-based anti-cancer chemotherapy is widely used to treat tumors. However, a large proportion of patients receiving these treatments will relapse because of metastasis and drug resistance. The purpose of this study is to explore the combinational anti-metastatic effect of platinum-based drugs and dihydroartemisinin (DHA). Both DDP and oxaliplatin (OXA) at low doses could induce epithelial-mesenchymal transition (EMT) in HCC. Meanwhile, co-administration of DHA could enhance DDP and OXA chemosensitivity in HCC and reverse drug resistance. DHA reversed the morphological changes induced by DDP or OXA and reversed the changes in EMT biomarkers induced by DDP and OXA in HCC in vitro and in vivo via AKT-Snail signaling. DHA significantly increased platinum-based drug sensitivity and suppressed EMT induced by platinum-based drugs via AKT-Snail signaling in HCC. DHA is expected to become the new adjuvant for chemotherapy.
