ABSTRACT
It was shown that some nanomaterials may have anticancer properties, but lack of selectivity is one of challenges, let alone selective suppression of cancer growth by regulating the cellular microenvironment. Herein, we demonstrated for the first time that carbon quantum dots/Cu2O composite (CQDs/Cu2O) selectively inhibited ovarian cancer SKOV3 cells by targeting cellular microenvironment, such as matrix metalloproteinases, angiogenic cytokines and cytoskeleton. The result was showed CQDs/Cu2O possessed anticancer properties against SKOV3 cells with IC50 = 0.85 µg mL-1, which was approximately threefold lower than other tested cancer cells and approximately 12-fold lower than normal cells. Compared with popular anticancer drugs, the IC50 of CQDs/Cu2O was approximately 114-fold and 75-fold lower than the IC50 of commercial artesunate (ART) and oxaliplatin (OXA). Furthermore, CQDs/Cu2O possessed the ability to decrease the expression of MMP-2/9 and induced alterations in the cytoskeleton of SKOV3 cells by disruption of F-actin. It also exhibited stronger antiangiogenic effects than commercial antiangiogenic inhibitor (SU5416) through down-regulating the expression of VEGFR2. In addition, CQDs/Cu2O has a vital function on transcriptional regulation of multiple genes in SKOV3 cells, where 495 genes were up-regulated and 756 genes were down-regulated. It is worth noting that CQDs/Cu2O also regulated angiogenesis-related genes in SKOV3 cells, such as Maspin and TSP1 gene, to suppress angiogenesis. Therefore, CQDs/Cu2O selectively mediated of ovarian cancer SKOV3 cells death mainly through decreasing the expression of MMP-2, MMP-9, F-actin, and VEGFR2, meanwhile CQDs/Cu2O caused apoptosis of SKOV3 via S phase cell cycle arrest. These findings reveal a new application for the use of CQDs/Cu2O composite as potential therapeutic interventions in ovarian cancer SKOV3 cells.
Subject(s)
Carbon/pharmacology , Cell Death/drug effects , Cytokines/metabolism , Cytoskeleton/metabolism , Matrix Metalloproteinases/metabolism , Nanocomposites/chemistry , Ovarian Neoplasms/drug therapy , Quantum Dots/chemistry , Angiogenesis Inducing Agents , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Copper/chemistry , Copper/pharmacology , Down-Regulation/drug effects , Female , Humans , Matrix Metalloproteinase 9/metabolism , Mice , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Though metal-organic frameworks (MOFs) have inspired potential applications in biomedicine, cytotoxicity studies of MOFs have been relatively rare. Here we demonstrate for the first time that an easily available MOF, Fe-MIL-101, possesses intrinsic activity against human SKOV3 ovarian cancer cells and suppress the proliferation of SKOV3 cells (IC50 = 23.6 µg mL(-1)) and normal mouse embryonic fibroblasts (BABL-3T3, IC50 = 78.3 µg mL(-1)) cells. It was more effective against SKOV3 cells than typical anticancer drugs such as artesunate (ART, IC50 = 96.9 µg mL(-1)) and oxaliplatin (OXA, IC50 = 64.4 µg mL(-1)), but had less effect on normal BABL-3T3 cells compared with ART (IC50 = 36.6 µg mL(-1)) and OXA (IC50 = 13.8 µg mL(-1)). Fe-MIL-101 induced apoptosis of human umbilical vein endothelial cells (HUVECs) via G0/G1 cell cycle arrest and decreased the mitochondrial membrane potential in HUVECs and induced apoptosis. Furthermore, Fe-MIL-101 exhibited stronger antiangiogenic effects in HUVEC cells than antiangiogenic inhibitor (SU5416) via downregulation the expression of MMP-2/9. Our results reveal a new role of Fe-MIL-101 as a novel, non-toxic anti-angiogenic agent that restricted ovarian tumour growth. These findings could open a new avenue of using MOFs as potential therapeutics in angiogenesis-dependent diseases, including ovarian cancer.
