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: Gen Zhang, Lei Ding, Randall Renegar, Xuemei Wang, Qun Lu, Shouquan Huo, Yan-Hua Chen
• Journal: Cancer science (Cancer Sci) Vol. 102 Issue 6 Pg. 1216-22 (Jun 2011) ISSN: 1349-7006 [Electronic] England
• PMID: 21435100 (Publication Type: Journal Article)
• Copyright: © 2011 Japanese Cancer Association.

Chemical References

• Antineoplastic Agents, Phytogenic
• Cadherins
• Claudins
• Ferrous Compounds
• Membrane Proteins
• Phosphoproteins
• TJP1 protein, human
• Zonula Occludens-1 Protein
• 10-hydroxycamptothecin
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Caspase 8
• ferrous oxide
• Camptothecin

Topics

• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacology)
• Apoptosis
• Cadherins (biosynthesis)
• Camptothecin (administration & dosage, analogs & derivatives, pharmacology)
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Claudins (biosynthesis)
• Drug Delivery Systems (methods)
• Ferrous Compounds
• Humans
• Immunoblotting
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Lung Neoplasms (drug therapy, pathology)
• Membrane Potentials (drug effects)
• Membrane Proteins (biosynthesis)
• Nanoparticles
• Phosphoproteins (biosynthesis)
• Phosphorylation (drug effects)
• Tight Junctions (drug effects, ultrastructure)
• X-Ray Diffraction
• Zonula Occludens-1 Protein
• p38 Mitogen-Activated Protein Kinases (metabolism)