title: Hydroxycamptothecin-loaded Fe3O4 nanoparticles induce human lung cancer cell apoptosis through caspase-8 pathway activation and disrupt tight junctions.
abstract: 10-Hydroxycamptothecin (HCPT) elicits strong anti-cancer effects and is less toxic than camptothecin (CPT), making it widely used in recent clinical trials. However, its low solubility limits its application as an effective anti-cancer therapy. In the present study we investigate the hypothesis that the unique water dispersible oleic acid-Triton X-100-coated Fe3O4 nanoparticles loaded with HCPT disrupt epithelial cell-cell junctions and induce human lung cancer cell apoptosis through the caspase-8 pathway. We characterized the HCPT-loaded nanoparticles and determined their effects on lung cancer cell viability and apoptosis by using immunofluorescence light microscopy and SDS-PAGE/immunoblots. We found that HCPT-loaded nanoparticles elicited an anti-proliferative effect in a dose-dependent manner. HCPT-loaded nanoparticles reduced the expression of cell-cell junction protein claudins, E-cadherin and ZO-1, and transmission electron microcopy demonstrated a disrupted tight junction ultrastructure. Transepithelial electric resistance was also reduced, indicating the reduction of tight junction functions. The HCPT-loaded nanoparticles increased phosphorylation of p38 and SAPK/JNK while it showed no effects on p42/44 MAP kinase. Compared with void Fe3O4 nanoparticles or HCPT drug alone, HCPT drug-loaded nanoparticles evoked synergistic effects by increasing cell apoptosis with enhanced activation of the caspase-8 pathway. Therefore, our current study highlights the potential of HCPT drug-loaded nanoparticles as a chemotherapeutic agent for increasing anti-cancer drug efficacy.
authors: Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA.
authors: Gen
authors: G
authors: Zhang
authors: Lei
authors: L
authors: Ding
authors: Randall
authors: R
authors: Renegar
authors: Xuemei
authors: X
authors: Wang
authors: Qun
authors: Q
authors: Lu
authors: Shouquan
authors: S
authors: Huo
authors: Yan-Hua
authors: YH
authors: Chen
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D015820:Cadherins / Q000096:biosynthesis; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057167:Claudins / Q000096:biosynthesis; D016503:Drug Delivery Systems / Q000379:methods*; D005296:Ferrous Compounds; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000096:biosynthesis; D053758:Nanoparticles; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects / Q000648:ultrastructure; D014961:X-Ray Diffraction; D062826:Zonula Occludens-1 Protein; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D015820:Cadherins; D057167:Claudins; D005296:Ferrous Compounds; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C028098:10-hydroxycamptothecin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8; C034236:ferrous oxide; D002166:Camptothecin