ABSTRACT
Alkyl esters of gallic acid inhibited the respiration rate of mouse sarcoma 786A and mouse mammary adenocarcinoma TA3 cell lines and its multiresistant variant TA3-MTX-R more effectively than gallic acid, both in the absence and in the presence of the uncoupler CCCP. The order of inhibition of the respiration rate by gallates in intact cells was n-octyl- approximately iso-amyl- approximately n-amyl- approximately iso-butyl->n-butyl->iso-propyl->n-propyl-gallate>>gallic acid. Sarcoma 786A was significantly more susceptible to all seven esters than the TA3 cell line. Respiration rates of the TA3-MTX-R cell line showed almost the same sensitivity to these esters as the TA3 cell line. However, hepatocytes were significantly less sensitive than all tumor cells tested. These alkyl gallates blocked mitochondrial electron flow, mainly at the NADH-CoQ segment, preventing ATP synthesis, which would lead to cellular death. These esters also inhibited, in the same order of potencies as respiration, the growth of 786A, TA3 and TA3-MTX-R cells in culture. In mice carrying TA3 or TA3-MTX-R tumor cells, an important decrease of the tumor growth rate and an increase of survival were observed when mice were treated with iso-butyl gallate alone or in combination with doxorubicin. These results indicate that alkyl gallates are selectively cytotoxic to tumor cells, which may be due to the mitochondrial dysfunctions of these cells.
Subject(s)
Antineoplastic Agents/pharmacology , Hepatocytes/drug effects , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Respiration/drug effects , Cells, Cultured , Drug Screening Assays, Antitumor , Electron Transport , Gallic Acid/analogs & derivatives , Gallic Acid/pharmacology , Mice , Mitochondria, Liver/drug effects , Mitochondria, Liver/metabolism , Propyl Gallate/pharmacology , Rats , Toxicity TestsABSTRACT
The effects of some imine and amine derivatives of vanillin on the respiration rate of mouse mammary adenocarcinoma TA3 line, its multiresistant variant TA3-MTX-R line and mouse hepatocytes, together with their respective mitochondrial fractions, are described. These derivatives inhibit respiration in both tumour cell lines more effectively than vanillin in the absence or presence of the uncoupler CCCP. Since both types of derivatives block the electron flow, mainly through the NADH-CoQ span, they behave as oxidative phosphorylation inhibitors. Thus, they prevent ATP synthesis and alter cellular processes requiring energy, which would lead to cellular death. Amine derivatives of vanillin present a similar effect on both tumour cell lines, being amine C the most efficient inhibitor. Moreover, mouse hepatocytes are about 4-fold less sensitive to amine C than tumour cells. These amine derivatives are better inhibitors than the corresponding imines; probably because they should interact better with the respiratory chain reaction site.