title: Pretubulysin: a new option for the treatment of metastatic cancer.
abstract: 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.
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Braig
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: R M
authors.initials: RM
authors.lastname: Wiedmann
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Liebl
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Singer
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Kubisch
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Schreiner
authors.affiliation: Institute for Experimental Research in Pediatrics, University Hospital Frankfurt, Komturstrasse 3a, 60528 Frankfurt aM, Germany.
authors.forename: B A
authors.initials: BA
authors.lastname: Abhari
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Wagner
authors.affiliation: Institute for Organic Chemistry, Saarland University, PO Box 151150, 66041 Saarbrücken, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Kazmaier
authors.affiliation: Institute for Experimental Research in Pediatrics, University Hospital Frankfurt, Komturstrasse 3a, 60528 Frankfurt aM, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Fulda
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Vollmar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009842:Oligopeptides / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D009842:Oligopeptides; D048031:JNK Mitogen-Activated Protein Kinases; C575012:pretubulysin