Pretubulysin : a new option for the treatment of metastatic cancer

  • 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.

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Author:Simone Braig, Romina Madeleine Wiedmann, Johanna Liebl, M. Singer, Rebekka Kubisch, Laura Schreiner, Behnaz Abhari, Ernst Wagner, Uli Kazmaier, Simone FuldaORCiDGND, Angelika Vollmar
URN:urn:nbn:de:hebis:30:3-347005
DOI:https://doi.org/10.1038/cddis.2013.510
ISSN:2041-4889
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/24434509
Parent Title (English):Cell death & disease
Publisher:Nature Publishing Group
Place of publication:London [u. a.]
Contributor(s):A. Stephanou
Document Type:Article
Language:English
Year of Completion:2014
Date of first Publication:2014/01/16
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2014/10/29
Tag:Fbw7; Mcl-1; TRAIL; metastatic cancer; microtubule-targeting agents; natural compounds
Volume:5
Issue:e1001
Page Number:11
First Page:1
Last Page:11
Note:
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/
HeBIS-PPN:366619136
Institutes:Biowissenschaften / Biowissenschaften
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universit├Ątspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Keine kommerzielle Nutzung-Weitergabe unter gleichen Bedingungen