ABSTRACT
The cyclic chalcone analogue, E-2-(4'-methoxybenzylidene)-1-benzosuberone (MBB), has been found to show outstanding in vitro cytotoxic activity against P388, L1210, Molt 4/C8 and CEM cells, as well as against a panel of human cell lines. In order to determine whether this promising antineoplastic activity would extend to anticarcinogenic properties, the effect of MBB on the 7,12-dimethylbenz [alpha]anthracene (DMBA)-induced expression of the c-myc, Ha-ras and p53 genes in isolated RNA from the liver, lung, kidney, spleen, thymus, lymph nodes and bone marrow of CBA/Ca inbred mice was investigated. Earlier we had found that administration of MBB can reduce the DMBA-induced 24-hour gene expressions most effectively when it is administered prior to, or simultaneously with, the DMBA-treatment to female CBA/Ca inbred mice. As a continuation of this study, we investigated the effect of MBB on the DMBA-induced gene expressions according to the two protocols in a 48-hour experiment. The 48-hour experiment with female and male CBA/Ca inbred mice also determined the compound which effectively reduced the DMBA-induced c-myc and Ha-ras overexpressions in almost all tissues. While the DMBA-induced gene expressions showed very different patterns, the effectiveness of the two different administrations of MBB was found to be very similar in the two sex groups. At the same time, contrary to the 24-hour experiment, increased p53 gene expression levels could be seen in several tissues in both sex groups. In order to get a better understanding of the effects of MBB on the DMBA-induced gene expressions "long-term" and "follow-up" studies should be performed.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene/toxicity , Anisoles/pharmacology , Anticarcinogenic Agents/pharmacology , Cycloheptanes/pharmacology , Oncogenes/drug effects , Tumor Suppressor Protein p53/metabolism , Animals , Carcinogens/toxicity , Drug Interactions , Female , Genes, ras/drug effects , Humans , Male , Mice , Mice, Inbred CBA , Oncogenes/physiology , Proto-Oncogene Proteins c-myc/drug effects , Proto-Oncogene Proteins c-myc/metabolism , Tumor Suppressor Protein p53/drug effectsABSTRACT
The cyclic chalcone analogue, E-2-(4'-methoxybenzylidene)-1-benzosuberone (MBB), was found to show outstanding in vitro antineoplastic activity against P388, L1210, Molt 4/C8 and CEM cells as well as against a panel of human tumor cell lines. In order to determine whether this promising antineoplastic activity would extend to anticarcinogenic properties, the effects of MBB on the 7,12-dimethylbenz[alpha] anthracene (DMBA)-induced expression of c-myc, Ha-ras and p53 genes in isolated RNA from liver, lung, kidney, spleen, thymus, lymph nodes and bone marrow of CBA/Ca inbred mice was investigated. DMBA is a well-known chemical carcinogen, which can act as an initiator by causing point mutations in certain oncogenes and tumor suppressor genes. Elevated expression of oncogenes after treatment with DMBA and other carcinogenic chemicals has been noted previously. Administration of MBB simultaneously with DMBA, 24 hours prior to or 24 hours after the DMBA treatment characteristically modified the DMBA-induced expression of the three genes in the 24-hour experiments. The most pronounced suppression effect of MBB could be observed in almost all the investigated tissues when it was administered simultaneously with DMBA. These "short-term" in vivo results support our previous conclusion that MBB can serve as a model molecule for subsequent structural modifications in searching for new effective anticarcinogenic agents.