Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner

0446714 - BTÚ 2016 RIV GB eng J - Článek v odborném periodiku
Yan, B. - Stantic, M. - Zobalová, Renata - Bezawork-Geleta, A. - Stapelberg, M. - Stursa, J. - Prokopová, Kateřina - Dong, L. - Neužil, Jiří
Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner.
Bmc Cancer. Roč. 15, č. 401 (2015). E-ISSN 1471-2407
Grant CEP: GA MZd NT14078; GA MŠMT(CZ) ED1.1.00/02.0109
Institucionální podpora: RVO:86652036
Klíčová slova: Tumour-initiating cells * Mitochondrially targeted vitamin E succinate * Complex II
Kód oboru RIV: FD - Onkologie a hematologie
Impakt faktor: 3.265, rok: 2015

Background: Accumulating evidence suggests that breast cancer involves tumour-initiating cells (TICs), which play a role in initiation, metastasis, therapeutic resistance and relapse of the disease. Emerging drugs that target TICs are becoming a focus of contemporary research. Mitocans, a group of compounds that induce apoptosis of cancer cells by destabilising their mitochondria, are showing their potential in killing TICs. In this project, we investigated mitochondrially targeted vitamin E succinate (MitoVES), a recently developed mitocan, for its in vitro and in vivo efficacy against TICs. Methods: The mammosphere model of breast TICs was established by culturing murine NeuTL and human MCF7 cells as spheres. This model was verified by stem cell marker expression, tumour initiation capacity and chemotherapeutic resistance. Cell susceptibility to MitoVES was assessed and the cell death pathway investigated. In vivo efficacy was studied by grafting NeuTL TICs to form syngeneic tumours. Results: Mammospheres derived from NeuTL and MCF7 breast cancer cells were enriched in the level of stemness, and the sphere cells featured altered mitochondrial function. Sphere cultures were resistant to several established anti-cancer agents while they were susceptible to MitoVES. Killing of mammospheres was suppressed when the mitochondrial complex II, the molecular target of MitoVES, was knocked down. Importantly, MitoVES inhibited progression of syngeneic HER2(high) tumours derived from breast TICs by inducing apoptosis in tumour cells. Conclusions: These results demonstrate that using mammospheres, a plausible model for studying TICs, drugs that target mitochondria efficiently kill breast tumour-initiating cells.
Trvalý link: http://hdl.handle.net/11104/0248779