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 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.

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-C-pPhC(6)H(5) combination in lung cancer treatment.

• Authors: Nkechi Ichite, Mahavir B Chougule, Tanise Jackson, Suniket V Fulzele, Stephen Safe, Mandip Singh
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 2 Pg. 543-52 (Jan 15 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19147759 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Indoles
• Taxoids
• Docetaxel
• Poly(ADP-ribose) Polymerases
• Caspase 3
• 3,3'-diindolylmethane

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Docetaxel
• Drug Synergism
• Female
• Humans
• Indoles (chemistry)
• Lung Neoplasms (drug therapy)
• Mice
• Neoplasm Transplantation
• Poly(ADP-ribose) Polymerases (metabolism)
• Taxoids (pharmacology)