Inhalation Delivery of a Novel Diindolylmethane Derivative for the Treatment of Lung Cancer

摘要

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 (Doc) 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, Doc, or combination (DIM-C-pPhC6H5 plus Doc) using a nose-only exposure technique. The aerodynamic properties included mass median aerodynamic diameter of 1.8 ± 0.3 μm and geometric standard deviation of 2.31 ± 0.02. Lung weight reduction in mice treated with the drug combination was 64 % compared to 40 % and 47 % in mice treated with DIM-C-pPhC6H5 aerosol and Doc alone respectively. Combination treatment decreased expression of akt, cyclinD1, survivin, Mcl-1, NF-kB, IKBα, P-IkBα, VEGF, and increased expression of JNK2 and Bad compared to tumors collected from single-agent treatment and control groups. DNA fragmentation was also enhanced in mice treated with the drug combination mice compared to Doc or DIM-C-pPhC6H5 alone. Combination treatment decreased expressions of VEGF & CD31 compared to single agent treated and control groups. These results suggest that DIM-C-pPhC6H5 aerosol enhanced the anticancer activity of Doc 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.