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

Abstract

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.

Pharmacological modulation of mitochondrial ion channels

“…Indeed, some of these compounds are already in clinical trials; others have been tested in vitro in tumour cell lines or in vivo in preclinical models for different neoplasms. Some of these molecules are mastoparan‐like peptides (Jones et al ., ), 4‐( N ‐(Sglutathionylacetyl)amino)phenylarsonous acid (Elliott et al ., ), ursolic acid (Lu et al ., ), betulinic acid (Fulda et al ., ; Potze et al ., ), B4G2 (an hydroxybetulinic acid derivative) (Yao et al ., ), triterpenoid derivatives (Laszczyk, ; Serafim et al ., ), curcumin (Qiu et al ., ), lonidamine (Lena et al ., ), ABT‐737 (a BH3 mimetic) (Yu et al ., ), the K + /H + antiporter salinomycin (Manago et al ., ; Qin et al ., ), berberine (Shen et al ., ), ebselen (Pavon et al ., ), the gold complex AUL‐12 (Chiara et al ., ), icaritin (Zhou et al ., ), EM20‐25 (Milanesi et al ., ) and ferutinin (Ilyich et al ., ). It has to be stressed that in most cases, possible side effects can be envisioned as opening of the PTP might lead to loss of mitochondrial function in healthy cells as well.…”

Synthesis of N-Heterocyclic Analogues of 28-O-Methyl Betulinate, and Their Antibacterial and Antifungal Properties

“…and some coenzymes. In studies of N-heterocycles, quaternary ammonium compounds and their reduction products-1,2,5,6-tetrahydropyridines-are of particular interest as they can act as membrane-active substances exhibiting antitumor and antimicrobial properties [2,3].…”

Assessing the potential impact of a biorefinery product from sawmill residues on the profitability of a hardwood value chain

“…anti-cancer and anti-HIV action (Alakurtti et al 2006;Gong et al 2004;Pavlova et al 2003; 89 Serafim et al 2014;Tolstikov et al 2005). Betulin and its derivates have also been used in 90 cosmetics and personal care products for years, and research is being continuously done to assess 91 their pharmacological properties (Krasutsky 2006;Royer et al 2012).…”