Thiostrepton

Thiazole antibiotic thiostrepton is an inhibitor of Forkhead box M1 (FOXM1), which effectively reduces cancer cell growth through downregulation of FOXM1. FOXM1 is a transcription factors that regulate expression of genes involved in maintenance of genomic stability and cell cycle progression.

In vitro: Thiostrepton inhibits the transcriptional activity and FOXM1 expression, and induces strong apoptosis in human cancer cells of different origin that correlates with suppression of FOXM1, including leukemia, neuroblastoma, liver cancer, melanoma and prostate cancer cells. Thiostrepton binds FOXM1 on the promoter site to inhibit transcriptional activity of FOXM1 through the FOXM1 autoregulation mechanism [1].

In vivo: Thiostrepton suppressed tumor growth in a human breast cancer xenograft model. Treatment with developed micelle-thiostrepton nanoparticles decreased xenograft tumor growth induced by the human MDA-MB-231 breast and HepG2 liver cancer cell lines. These apoptosis activities in drug-treated tumors were correlated with in vivo suppression of oncogenic FOXM1 [1].

Clinical trial: So far, no clinical study has been conducted.

Reference:
[1] Gartel AL.  Suppression of the Oncogenic Transcription Factor FOXM1 by Proteasome Inhibitors. Scientifica (Cairo). 2014;2014:596528.

Inhibition of Sonic Hedgehog Signaling Pathway by Thiazole Antibiotic Thiostrepton Attenuates the CD44+/CD24-Stem-Like Population and Sphere-Forming Capacity in Triple-Negative Breast Cancer.[Pubmed:26963129]

Cell Physiol Biochem. 2016;38(3):1157-70.

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) represents a particular clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The lack of effective agents and obvious targets are major challenges in treating TNBC. In this study we explored the cytostatic effect of thiazole ring containing antibiotic drug Thiostrepton on TNBC cell lines and investigated the molecular mechanism. METHODS: Cell viability was measured by MTT assay. Cell surface marker was monitored by FCM. Western blot was applied to assess the protein expression levels of target genes. RESULTS: We found that Thiostrepton remarkably suppressed the CD44+/CD24- stem-like population and sphere forming capacity of TNBC cell lines. Notably, we showed for the first time that Thiostrepton exerted its pharmacological action by targeting sonic hedgehog (SHH) signaling pathway. Thiostrepton repressed SHH ligand expression and reduced Gli-1 nuclear localization in TNBC cell line. Furthermore, the downstream target of SHH signaling undergone dose-dependent, rapid, and sustained loss of mRNA transcript level after Thiostrepton treatment. Finally, we showed that SHH ligand was essential for maintaining CD44+/CD24- stem-like population in TNBC cell line. CONCLUSION: We conclude that Thiostrepton suppresses the CD44+/CD24- stem-like population through inhibition of SHH signaling pathway. Our results give a new insight into the mechanism of Thiostrepton anti-tumor activity and suggest Thiostrepton as a promising agent that targets hedgehog signaling pathway in TNBC.

Precursor-Directed Mutational Biosynthesis Facilitates the Functional Assignment of Two Cytochromes P450 in Thiostrepton Biosynthesis.[Pubmed:27560135]

ACS Chem Biol. 2016 Oct 21;11(10):2673-2678.

Side-ring-modified Thiostrepton (TSR) derivatives that vary in their quinaldic acid (QA) substitution possess more potent biological activities and better pharmaceutical properties than the parent compound. In this work, we sought to introduce fluorine onto C-7' or C-8' of the TSR QA moiety via precursor-directed mutational biosynthesis to obtain new TSR variants. Unexpectedly, instead of the target product, the exogenous chemical feeding of 7-F-QA into the DeltatsrT mutant strain resulted in a unique TSR analog with an incomplete side-ring structure and an unoxidized QA moiety (1). Accordingly, two cytochrome P450 genes, tsrP and tsrR, were in-frame deleted to elucidate the candidate responsible for the monooxidation of the QA moiety in TSR. The unfluorinated analog of compound 1 that was thus isolated from DeltatsrP (2) and the abolishment of TSR production in DeltatsrR revealed not only the biosynthetic logic of the TSR side-ring but also the essential checkpoint in TSR maturation before macro-ring closure.

Complete Genome Sequence of Thiostrepton-Producing Streptomyces laurentii ATCC 31255.[Pubmed:27257211]

Genome Announc. 2016 Jun 2;4(3). pii: 4/3/e00360-16.

Streptomyces laurentii ATCC 31255 produces Thiostrepton, a thiopeptide class antibiotic. Here, we report the complete genome sequence for this strain, which contains a total of 8,032,664 bp, 7,452 predicted coding sequences, and a G+C content of 72.3%.

An alpha/beta-hydrolase fold protein in the biosynthesis of thiostrepton exhibits a dual activity for endopeptidyl hydrolysis and epoxide ring opening/macrocyclization.[Pubmed:27911800]

Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14318-14323.

Thiostrepton (TSR), an archetypal bimacrocyclic thiopeptide antibiotic that arises from complex posttranslational modifications of a genetically encoded precursor peptide, possesses a quinaldic acid (QA) moiety within the side-ring system of a thiopeptide-characteristic framework. Focusing on selective engineering of the QA moiety, i.e., by fluorination or methylation, we have recently designed and biosynthesized biologically more active TSR analogs. Using these analogs as chemical probes, we uncovered an unusual indirect mechanism of TSR-type thiopeptides, which are able to act against intracellular pathogens through host autophagy induction in addition to direct targeting of bacterial ribosome. Herein, we report the accumulation of 6'-fluoro-7', 8'-epoxy-TSR, a key intermediate in the preparation of the analog 6'-fluoro-TSR. This unexpected finding led to unveiling of the TSR maturation process, which involves an unusual dual activity of TsrI, an alpha/beta-hydrolase fold protein, for cascade C-N bond cleavage and formation during side-ring system construction. These two functions of TsrI rely on the same catalytic triad, Ser72-His200-Asp191, which first mediates endopeptidyl hydrolysis that occurs selectively between the residues Met-1 and Ile1 for removal of the leader peptide and then triggers epoxide ring opening for closure of the QA-containing side-ring system in a regio- and stereo-specific manner. The former reaction likely requires the formation of an acyl-Ser72 enzyme intermediate; in contrast, the latter is independent of Ser72. Consequently, C-6' fluorination of QA lowers the reactivity of the epoxide intermediate and, thereby, allows the dissection of the TsrI-associated enzymatic process that proceeds rapidly and typically is difficult to be realized during TSR biosynthesis.

Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression.[Pubmed:18645012]

Mol Cancer Ther. 2008 Jul;7(7):2022-32.

Elevated expression or activity of the transcription factor forkhead box M1 (FOXM1) is associated with the development and progression of many malignancies, including breast cancer. In this study, we show that the thiazole antibiotic Thiostrepton selectively induces cell cycle arrest and cell death in breast cancer cells through down-regulating FOXM1 expression. Crucially, our data show that Thiostrepton treatment reduced FOXM1 expression in a time- and dose-dependent manner, independent of de novo protein synthesis and predominantly at transcriptional and gene promoter levels. Our results indicate that Thiostrepton can induce cell death through caspase-dependent intrinsic and extrinsic apoptotic pathways as well as through caspase-independent death mechanisms, as observed in MCF-7 cells, which are deficient of caspase-3 and caspase-7. Cell cycle analysis showed that Thiostrepton induced cell cycle arrest at G(1) and S phases and cell death, concomitant with FOXM1 repression in breast cancer cells. Furthermore, Thiostrepton also shows efficacy in repressing breast cancer cell migration, metastasis, and transformation, which are all downstream functional attributes of FOXM1. We also show that overexpression of a constitutively active FOXM1 mutant, DeltaN-FOXM1, can abrogate the antiproliferative effects of Thiostrepton. Interestingly, Thiostrepton has no affect on FOXM1 expression and proliferation of the untransformed MCF-10A breast epithelial cells. Collectively, our data show that FOXM1 is one of the primary cellular targets of Thiostrepton in breast cancer cells and that Thiostrepton may represent a novel lead compound for targeted therapy of breast cancer with minimal toxicity against noncancer cells.

Thiostrepton inhibition of tRNA delivery to the ribosome.[Pubmed:17951333]

RNA. 2007 Dec;13(12):2091-7.

Ribosome-stimulated hydrolysis of guanosine-5'-triphosphate (GTP) by guanosine triphosphatase (GTPase) translation factors drives protein synthesis by the ribosome. Allosteric coupling of GTP hydrolysis by elongation factor Tu (EF-Tu) at the ribosomal GTPase center to messenger RNA (mRNA) codon:aminoacyl-transfer RNA (aa-tRNA) anticodon recognition at the ribosomal decoding site is essential for accurate and rapid aa-tRNA selection. Here we use single-molecule methods to investigate the mechanism of action of the antibiotic Thiostrepton and show that the GTPase center of the ribosome has at least two discrete functions during aa-tRNA selection: binding of EF-Tu(GTP) and stimulation of GTP hydrolysis by the factor. We separate these two functions of the GTPase center and assign each to distinct, conserved structural regions of the ribosome. The data provide a specific model for the coupling between the decoding site and the GTPase center during aa-tRNA selection as well as a general mechanistic model for ribosome-stimulated GTP hydrolysis by GTPase translation factors.

Thiostrepton is a natural cyclic oligopeptide antibiotic, is a natural product of the ribosomally synthesized and post-translationally modified peptide (RiPP) class.

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