Purpose: This study was conducted to examine the cytotoxic effects of a peroxisome proliferator-activated receptor g (PPARg) agonist, 1,1-bis (3 ¶-indolyl)-1-(p-biphenyl) methane (DIM-CpPhC 6 H 5 ), alone and in combination with docetaxel in vitro in A549 lung cancer cells and in vivo in nude mice bearing A549 orthotopic lung tumors. Experimental Design: Isobolographic method was used to calculate combination index values from cell viability data. Apoptosis was evaluated in A549 cells by terminal deoxynucleotidyl transferase-mediated nick end labeling assay and measurement of cleaved poly(ADP-ribose) polymerase level. Expression of proteins was studied by Western blotting. A549 cells were implanted to induce orthotopic lung tumors in nude mice and the efficacy of docetaxel, DIM-C-pPhC 6 H 5 , or combination was determined. Apoptosis and cleaved caspase-3 expression in the harvested tissues were studied by terminal deoxynucleotidyl transferase-mediated nick end labeling and immunohistochemistry, respectively. Results: The combination index values (0.36-0.9) suggested synergistic to additive effects of docetaxel + DIM-C-pPhC 6 H 5 and resulted in the highest increase in percentage of apoptotic cells and expression of cleaved poly(ADP-ribose) polymerase, Bax, and N-cadherin compared with treatment with either agent. The combination also enhanced procaspase-3 and -9 cleavage. In vivo, docetaxel + DIM-C-pPhC 6 H 5 reduced lung weights by 57% compared with 39% by docetaxel or 22% by DIM-C-pPhC 6 H 5 alone, induced apoptosis in 43% of the tumor cells compared with 29% and 22% in tumors treated with docetaxel and DIM-C-pPhC 6 H 5 , respectively, and increased procaspase-3 cleavage compared with either agent alone. Conclusions: These findings suggest potential benefit for use of docetaxel and DIM-CpPhC 6 H 5 combination in lung cancer treatment.
Our studies suggest that potent antitumor activity of Nos against NSCLC cells. Oral administration of Nos showed significant reduction in tumor volume in human non-small cell lung tumor xenograft in nude mice in a dose dependant manner. Thus, Nos is a promising novel chemotherapeutic agent for the treatment of human lung cancer.
The purpose of this study was to determine the anticancer efficacy of 1,1-bis (3′-indolyl)-1-(p-biphenyl) methane (DIM-C-pPhC 6 H 5 ) by inhalation delivery alone and in combination with i.v. docetaxel in a murine model for lung cancer. An aqueous DIM-C-pPhC 6 H 5 formulation was characterized for its aerodynamic properties. Tumor-bearing athymic nude mice were exposed to nebulized DIM-C-pPhC 6 H 5 , docetaxel, or combination (DIM-C-pPhC 6 H 5 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-pPhC 6 H 5 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 NH 2 -terminal kinase 2 and Bad compared with tumors collected from singleagent treatment and control groups. DNA fragmentation was also enhanced in mice treated with the drug combination compared with docetaxel or DIM-C-pPhC 6 H 5 alone. Combination treatment decreased expressions of VEGF and CD31 compared with single-agent treated and control groups. These results suggest that DIM-C-pPhC 6 H 5 aerosol enhanced the anticancer activity of docetaxel in a lung cancer model by activating multiple signaling pathways. The study provides evidence that DIM-C-pPhC 6 H 5 can be used alone or in combination with other drugs for the treatment of lung cancer using the inhalation delivery approach.
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