Rohlenova 2015 Abstract MiP2015
|Mitochondrial targeting of tamoxifen enhances its activity against Her2high breast cancer.|
Mitochondria play a crucial role for apoptosis induction in cancer cells. Tamoxifen is an established anti-cancer agent used primarily against hormone-dependent breast cancer. Here we present its mitochondrially targeted analogue, MitoTamoxifen (MitoTAM), generated by addition of the triphenyl phosphonium (TPP+) group to the parental compound. The mitochondrial delivery resulted in great increase of anti-cancer activity arising from extensive generation of reactive oxygen species. Importantly, in contrast to the parental compound, MitoTAM efficiently kills Her2high cells and suppresses experimental Her2high breast carcinomas in an animal model, such that the treatment leads to near complete disappearance of tumours. As a mechanism of this specificity, we document that Her2high cells comprise high amount of the Her2 protein in mitochondria, which results in increased level of mitochondrial respiratory complex I, the identified molecular target of MitoTAM. Mitochondrial targeting therefore not only improves efficacy of this anti-cancer agent, but also extends its applicability to cancer subtypes thus far recalcitrant to treatment.
Labels: MiParea: mt-Medicine, Pharmacology;toxicology Pathology: Cancer Stress:Oxidative stress;RONS
Enzyme: Complex I
Event: A2, Oral MiP2015
1-Inst Biotechn, Academy Sc Czech Republic, Prague, Czech Republic; 2-School Med Sc, Griffith Univ, Southport, Queensland, Australia; 3-Inst Chemical Technology, Prague, Czech Republic. - [email protected]