SYNERGISTIC EFFECTS OF COMBINATION OF COMPOUNDS IN CONTROLLING THE TUMOR DEVELOPMENT: INVOLVEMENT OF THE REGULATORS OF TUMORIGENESIS
Krishna P. Gupta
Carcinogenesis Laboratory, CSIR-Indian Institute of Toxicology Research, M. G. Marg, Lucknow-226001, India
Three compounds, Calcium D-glucarate, nicotinamide and butyric acid, were used as chemopreventive agents against dimethylbenzanthracene (DMBA) induced mouse skin tumorigenesis. Single compound inhibited the DMBA induced tumorigenesis by 33 to 47%, concomitant use of any two compounds showed 73-80 % and all the three compounds showed 100% inhibition. This could be due to the upregulation of the Caspases (3, 8 or 9), p16, p21 or downregulation of cox-2 or mtp53.
On - site application of single preparation of compounds inhibited the tumorigenesis by 90% in contrast to 30% protection by the administration in drinking water. Combination of either of two compounds was useful for chemoprevention. But three compounds together exhibited synergistic prevention when used concomitantly or as one mixture. However, the target site application of mixture appeared to be most effective suggesting the importance of the site directed therapies. Gene expression analysis suggested the involvement of apoptotic, cell cycle regulating and tumor suppressing genes in preventing the tumorigenesis as they are altered before and after the tumor development.
We provide a therapeutic rationale for agents activating non-cross-resistant pathways and targeting multiple pathways and show the importance of site targeted prevention by the combination of compounds of different nature.
Keywords: Skin tumor, prevention, combination, natural compounds, apoptosis and cell cycle.