TY  - JOUR
A1  - Braig, Simone
A1  - Wiedmann, Romina Madeleine
A1  - Liebl, Johanna
A1  - Singer, M.
A1  - Kubisch, Rebekka
A1  - Schreiner, Laura
A1  - Abhari, Behnaz
A1  - Wagner, Ernst
A1  - Kazmaier, Uli
A1  - Fulda, Simone
A1  - Vollmar, Angelika
T1  - Pretubulysin : a new option for the treatment of metastatic cancer
T2  - Cell death & disease
N2  - Tubulin-binding agents such as taxol, vincristine or vinblastine are well-established drugs in clinical treatment of metastatic cancer. However, because of their highly complex chemical structures, the synthesis and hence the supply issues are still quite challenging. Here we set on stage pretubulysin, a chemically accessible precursor of tubulysin that was identified as a potent microtubule-binding agent produced by myxobacteria. Although much simpler in chemical structure, pretubulysin abrogates proliferation and long-term survival as well as anchorage-independent growth, and also induces anoikis and apoptosis in invasive tumor cells equally potent to tubulysin. Moreover, pretubulysin posseses in vivo efficacy shown in a chicken chorioallantoic membrane (CAM) model with T24 bladder tumor cells, in a mouse xenograft model using MDA-MB-231 mammary cancer cells and finally in a model of lung metastasis induced by 4T1 mouse breast cancer cells. Pretubulysin induces cell death via the intrinsic apoptosis pathway by abrogating the expression of pivotal antiapoptotic proteins, namely Mcl-1 and Bcl-xL, and shows distinct chemosensitizing properties in combination with TRAIL in two- and three-dimensional cell culture models. Unraveling the underlying signaling pathways provides novel information: pretubulysin induces proteasomal degradation of Mcl-1 by activation of mitogen-activated protein kinase (especially JNK (c-Jun N-terminal kinase)) and phosphorylation of Mcl-1, which is then targeted by the SCF(Fbw7) E3 ubiquitin ligase complex for ubiquitination and degradation. In sum, we designate the microtubule-destabilizing compound pretubulysin as a highly promising novel agent for mono treatment and combinatory treatment of invasive cancer.
KW  - microtubule-targeting agents
KW  - natural compounds
KW  - metastatic cancer
KW  - Fbw7
KW  - Mcl-1
KW  - TRAIL
Y1  - 2014
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/34700
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-347005
SN  - 2041-4889
N1  - This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
VL  - 5
IS  - e1001
SP  - 1
EP  - 11
PB  - Nature Publishing Group
CY  - London [u. a.]
ER  -