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 SCFFbw7 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.
Highlights
In anticancer drug discovery, natural compounds have a long and successful history as reviewed by Newman and Cragg.[7,8] Natural compounds are a product of interest because of their enormous chemical diversity and biological activities appointing them as ‘privileged structures’
Epothilones produced by myxobacteria Sorangium cellulosum are the most prominent example, as ixabepilone, a semisynthetic derivate has recently been approved by the US Food and Drug Administration for treatment of metastatic breast cancer.[13]
Classical proliferation assays that run for 72 h revealed that treatment of the highly aggressive and metastatic cancer cell lines T24 and MDA-MB-231 with pretubulysin at low nanomolar concentrations results in inhibition of proliferation, which is comparable to the effect of tubulysin A
Summary
Natural compounds have a long and successful history as reviewed by Newman and Cragg.[7,8] Natural compounds are a product of interest because of their enormous chemical diversity and biological activities appointing them as ‘privileged structures’. An apparent obstacle of natural products is their supply, production and isolation as well as their chemical synthesis that is very often rather complex.[9,10,11] Microbial sources such as actinomycetes and more recently myxobacteria are recognized as highly prolific producers of bioactive secondary metabolites, which open up biotechnological approaches to guarantee validated supply of novel experimental drug candidates in the battle against cancer.[12] Epothilones produced by myxobacteria Sorangium cellulosum are the most prominent example, as ixabepilone, a semisynthetic derivate has recently been approved by the US Food and Drug Administration for treatment of metastatic breast cancer.[13]. We propose pretubulysin as a potent and innovative experimental drug for metastatic cancer treatment, as pretubulysin induces apoptotic cell death in various cancer cell lines at nanomolar concentrations and inhibits metastasis and tumor growth in vitro and in vivo. Pretubulysinmediated downregulation of Mcl-1 provides the mechanistic base for a synergistic interaction with TRAIL (TNF-related apoptosis-inducing ligand), another candidate for adjuvant therapies for metastatic cancer.[21]
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