Virus-directed enzyme prodrug therapy and the assessment of the cytotoxic impact of some benzimidazole derivatives

Abstract

Virus-directed enzyme prodrug therapy is one of the major strategy of increasing cytotoxicity of bioreductive agents. This research intended to examine new selected benzimidazole derivatives as a substrate for nitroreductase, the enzyme involved in nitroreduction which is responsible to the production of cytotoxic metabolites. In this way, the selectivity and strength of cytotoxicity can be raised. The effect of benzimidazoles on virus transfected cells and non-virus transfected cells A549 cell line was established by Annexin V + propidium iodide test, western blot, and polymerase chain reaction analysis of specific pro- and anti-apoptotic proteins in the corresponding gene expression and additionally nitroreductase gene expression. Our results proved the pro-apoptotic properties of all tested compounds in normoxia and hypoxia, especially according to virused A549 cells where the time of exposition was reduced from 48 to 4 h. In this shorten period of time, the strongest activity was shown by N-oxide compounds with nitro-groups. The apoptosis was confirmed by generation of BAX gene and protein and reduction of BCL2 gene and protein.

Antiproliferative Aspect of Benzimidazole Derivatives’ Activity and Their Impact on NF-κB Expression

“…Qiu et al proved that NF-κB inhibitor BAY11-7082 blocks NF-κB transcription, and ER-mediated induction of cell proliferation upon its activity was reversed [21]. These data are useful in the development of therapy strategies for IBC, with ER-positive breast tumors usually resistant to endocrine therapy [24,25,26]. In the line with this evidence, the search for new potential inhibitors of NF-κB is necessary.…”

“…For breast and lung cancer, benzimidazoles showed pro-apoptotic activity, with bax gene transactivation leading to the induction of bax protein expression. Their bioreductive mechanism of action, with nitroreductase gene activation [26] together with NF-κB expression inhibition, potentially indicates their pro-drug engagement into antiproliferation pathway, which may help in the abolition of tumors’ chemotherapy resistance.…”