Dimethylaminopyridine derivatives of lupane triterpenoids cause mitochondrial disruption and induce the permeability transition

Telma C. Bernardo, Teresa Cunha-Oliveira, Teresa L. Serafim, Jon Holy, Dmytro Krasutsky, Oksana Kolomitsyna, Pavel Krasutsky, António M. Moreno, Paulo J. Oliveira

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7239-7249
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number23
DOIs
StatePublished - Dec 1 2013

Bibliographical note

Funding Information:
This work was supported by projects Pest-C/SAU/LA0001/2013–2014 and PTDC/QUI-QUI/101409/2008 funded by Fundação para a Ciência e a Tecnologia (FCT), Portugal, and cofinanced by: ‘COMPETE-Programa Operacional Factores de Competitividade’, QREN and European Union (FEDER-Fundo Europeu de Desenvolvimento Regional). T.C.-O. was supported by the FCT postdoctoral fellowship SFRH/BPD/34711/2007, T.L.S. supported by the FCT postdoctoral fellowship SFRH/BPD/75959/2011, both co-financed by POPH-Programa Operacional Potencial Humano, QREN and European Union.

Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.

Keywords

  • Breast cancer cell lines
  • Liver mitochondria
  • Mitochondrial depolarization
  • Mitochondrial permeability transition
  • Triterpenoid derivatives

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