Inhalation delivery of a novel diindolylmethane derivative for the treatment of lung cancer.

Abstract

The purpose of this study was to determine the anticancer efficacy of 1,1-bis (3'-indolyl)-1-(p-biphenyl) methane (DIM-C-pPhC₆H₅) by inhalation delivery alone and in combination with i.v. docetaxel in a murine model for lung cancer. An aqueous DIM-C-pPhC₆H₅ formulation was characterized for its aerodynamic properties. Tumor-bearing athymic nude mice were exposed to nebulized DIM-C-pPhC₆H₅, docetaxel, or combination (DIM-C-pPhC₆H₅ plus docetaxel) using a nose-only exposure technique. The aerodynamic properties included mass median aerodynamic diameter of 1.8 ± 0.3 μm and geometric SD of 2.31 ± 0.02. Lung weight reduction in mice treated with the drug combination was 64% compared with 40% and 47% in mice treated with DIM-C-pPhC₆H₅ aerosol and docetaxel alone, respectively. Combination treatment decreased expression of Akt, cyclin D1, survivin, Mcl-1, NF-κB, IκBα, phospho-IκBα, and vascular endothelial growth factor (VEGF) and increased expression of c-Jun NH₂-terminal kinase 2 and Bad compared with tumors collected from single-agent treatment and control groups. DNA fragmentation was also enhanced in mice treated with the drug combination compared with docetaxel or DIM-C-pPhC₆H₅ alone. Combination treatment decreased expressions of VEGF and CD31 compared with single-agent treated and control groups. These results suggest that DIM-C-pPhC₆H₅ aerosol enhanced the anticancer activity of docetaxel in a lung cancer model by activating multiple signaling pathways. The study provides evidence that DIM-C-pPhC₆H₅ can be used alone or in combination with other drugs for the treatment of lung cancer using the inhalation delivery approach.

• Authors: Nkechi Ichite, Mahavir Chougule, Apurva R Patel, Tanise Jackson, Stephen Safe, Mandip Singh
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 11 Pg. 3003-14 (Nov 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20978159 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2010 AACR.

Chemical References

• 1,1-bis(3'-indolyl)-1-(4-biphenyl)methane
• Antineoplastic Agents
• Indoles
• Nasal Sprays
• 3,3'-diindolylmethane

Topics

• Administration, Inhalation
• Animals
• Antineoplastic Agents (administration & dosage, adverse effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Line, Tumor
• Drug Delivery Systems
• Female
• Humans
• Indoles (administration & dosage, adverse effects, chemistry)
• Lung Neoplasms (drug therapy, pathology)
• Mice
• Mice, Nude
• Models, Biological
• Nasal Sprays
• Xenograft Model Antitumor Assays