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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.

SUBMITTER: Braig S

PROVIDER: S-EPMC4040707 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Pretubulysin: a new option for the treatment of metastatic cancer.

Braig S S Wiedmann R M RM Liebl J J Singer M M Kubisch R R Schreiner L L Abhari B A BA Wagner E E Kazmaier U U Fulda S S Vollmar A M AM

Cell death & disease 20140116

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 abrogat ...[more]

PMID: 24434509

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Project description:IntroductionPsoriatic arthritis (PsA) is an immune-mediated chronic inflammatory arthropathy associated with impaired physical function and reduced quality of life. Biologic therapies that target tumor necrosis factor (anti-TNF) have significantly improved clinical outcomes. Partial, non- and transient responses remain common comprising significant unmet clinical need. New therapies with novel modes of action are urgently required.ObjectivesThe interleukin (IL)-17 pathway has recently been attributed a critical role in the pathogenesis of spondyloarthritides. Herein, we review data from clinical studies with secukinumab, a novel fully human IgG1κ anti-IL-17A monoclonal antibody (mAb), in patients with active PsA.ResultsAcross two pivotal phase 3 studies, secukinumab provided significant and sustained reductions in the signs and symptoms of PsA, inhibition of radiographic progression, and improved patient-reported outcomes and measures of quality of life. The primary efficacy endpoint, a ≥20% improvement from baseline according to the American College of Rheumatology 20 (ACR20) response at Week 24, was significantly higher in patients treated with secukinumab compared with placebo, with improvements sustained through at least 52 weeks. Clinical benefits were seen with secukinumab regardless of concomitant methotrexate treatment and in patients who were either anti-TNF-naïve or who were inadequate responders to anti-TNF therapy. Secukinumab was well-tolerated, with a safety profile consistent with that previously reported in psoriasis trials. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and headache.ConclusionSecukinumab offers an effective new addition to the available treatment options for PsA. Regulatory submissions have been filed worldwide, with the first approvals recently obtained in Japan and Europe. Future studies are required to define the optimal timing and strategic use of this novel treatment modality.FundingNovartis Pharma.

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Pretubulysin: a new option for the treatment of metastatic cancer.

Publications

Pretubulysin: a new option for the treatment of metastatic cancer.

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