New derivatives of lupane triterpenoids disturb breast cancer mitochondria and induce cell death

Teresa L. Serafim, Filipa S. Carvalho, Telma C. Bernardo, Gonçalo C. Pereira, Edward Perkins, Jon Holy, Dmytro A. Krasutsky, Oksana N. Kolomitsyna, Pavel A. Krasutsky, Paulo J. Oliveira

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Novel cationic dimethylaminopyridine derivatives of pentacyclic triterpenes were previously described to promote mitochondrial depolarization and cell death in breast and melanoma cell lines. The objective of this work was to further investigate in detail the mechanism of mitochondrial perturbations, correlating those effects with breast cancer cell responses to those same agents. Initially, a panel of tumor and non-tumor cell lines was grown in high-glucose or glucose-free glutamine-containing media, the later forcing cells to synthesize ATP by oxidative phosphorylation only. Cell proliferation, cell cycle, cell death and mitochondrial membrane polarization were evaluated. Inhibition of cell proliferation was observed, accompanied by an arrest in the G1-cell cycle phase, and importantly, by loss of mitochondrial membrane potential. On a later time-point, caspase-9 and 3 activation were observed, resulting in cell death. For the majority of test compounds, we determined that cell toxicity was augmented in the galactose media. To investigate direct evidences on mitochondria isolated rat liver mitochondria were used. The results showed that the compounds were strong inducers of the permeability transition pore. Confirming our previous results, this work shows that the novel DMAP derivatives strongly interact with mitochondria, resulting in pro-apoptotic signaling and cell death.

Original languageEnglish (US)
Pages (from-to)6270-6287
Number of pages18
JournalBioorganic and Medicinal Chemistry
Issue number21
StatePublished - Nov 1 2014

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.


  • Bioenergetics
  • Breast cancer
  • Cell death
  • Cytotoxicity
  • Lupane triterpenoids derivatives
  • Mitochondrial physiology


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