title: Enhancement of docetaxel anticancer activity by a novel diindolylmethane compound in human non-small cell lung cancer.
abstract: OBJECTIVE
  This study was conducted to examine the cytotoxic effects of a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, 1,1-bis (3'-indolyl)-1-(p-biphenyl) methane (DIM-C-pPhC(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.
  
  
  METHODS
  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-C-pPhC(6)H(5) combination in lung cancer treatment.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences. Florida A&M University, Tallahassee, Florida 32307, USA.
authors.forename: Nkechi
authors.initials: N
authors.lastname: Ichite
authors.forename: Mahavir B
authors.initials: MB
authors.lastname: Chougule
authors.forename: Tanise
authors.initials: T
authors.lastname: Jackson
authors.forename: Suniket V
authors.initials: SV
authors.lastname: Fulzele
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D043823:Taxoids; D000077143:Docetaxel; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; C016392:3,3'-diindolylmethane