Enhancement of Docetaxel Anticancer Activity by a Novel Diindolylmethane Compound in Human Non–Small Cell Lung Cancer

Abstract

Purpose: This study was conducted to examine the cytotoxic effects of a peroxisome proliferator-activated receptor γ (PPARγ) agonist, 1,1-bis (3′-indolyl)-1-(p-biphenyl) methane (DIM-C-pPhC₆H₅), 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-pPhC₆H₅, 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-pPhC₆H₅ 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-pPhC₆H₅ reduced lung weights by 57% compared with 39% by docetaxel or 22% by DIM-C-pPhC₆H₅ alone, induced apoptosis in 43% of the tumor cells compared with 29% and 22% in tumors treated with docetaxel and DIM-C-pPhC₆H₅, respectively, and increased procaspase-3 cleavage compared with either agent alone. Conclusions: These findings suggest potential benefit for use of docetaxel and DIM-C-pPhC₆H₅ combination in lung cancer treatment.