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Title: Dimethylaminopyridine derivatives of lupane triterpenoids cause mitochondrial disruption and induce the permeability transition
Authors: Bernardo, Telma C. 
Cunha-Oliveira, Teresa 
Serafim, Teresa L. 
Holy, Jon 
Krasutsky, Dmytro 
Kolomitsyna, Oksana 
Krasutsky, Pavel 
Moreno, António M. 
Oliveira, Paulo J. 
Keywords: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Respiration; Female; Humans; Male; Melanoma; Membrane Potentials; Mitochondria, Liver; Mitochondrial Membrane Transport Proteins; Permeability; Pyridines; Rats; Rats, Wistar; Triterpenes
Issue Date: Dec-2013
Serial title, monograph or event: Bioorganic & Medicinal Chemistry
Volume: 21
Issue: 23
Abstract: Triterpenoids are a large class of naturally occurring compounds, and some potentially interesting as anticancer agents have been found to target mitochondria. The objective of the present work was to investigate the mechanisms of mitochondrial toxicity induced by novel dimethylaminopyridine (DMAP) derivatives of pentacyclic triterpenes, which were previously shown to inhibit the growth of melanoma cells in vitro. MCF-7, Hs 578T and BJ cell lines, as well as isolated hepatic mitochondria, were used to investigate direct mitochondrial effects. On isolated mitochondrial hepatic fractions, respiratory parameters, mitochondrial transmembrane electric potential, induction of the mitochondrial permeability transition (MPT) pore and ion transport-dependent osmotic swelling were measured. Our results indicate that the DMAP triterpenoid derivatives lead to fragmentation and depolarization of the mitochondrial network in situ, and to inhibition of uncoupled respiration, induction of the permeability transition pore and depolarization of isolated hepatic mitochondria. The results show that mitochondrial toxicity is an important component of the biological interaction of DMAP derivatives, which can explain the effects observed in cancer cells.
DOI: 10.1016/j.bmc.2013.09.066
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

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