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Heterotaxin: a TGF-? signaling inhibitor identified in a multi-phenotype profiling screen in Xenopus embryos.

ABSTRACT: Disruptions of anatomical left-right asymmetry result in life-threatening heterotaxic birth defects in vital organs. We performed a small molecule screen for left-right asymmetry phenotypes in Xenopus embryos and discovered a pyridine analog, heterotaxin, which disrupts both cardiovascular and digestive organ laterality and inhibits TGF-?-dependent left-right asymmetric gene expression. Heterotaxin analogs also perturb vascular development, melanogenesis, cell migration, and adhesion, and indirectly inhibit the phosphorylation of an intracellular mediator of TGF-? signaling. This combined phenotypic profile identifies these compounds as a class of TGF-? signaling inhibitors. Notably, heterotaxin analogs also possess highly desirable antitumor properties, inhibiting epithelial-mesenchymal transition, angiogenesis, and tumor cell proliferation in mammalian systems. Our results suggest that assessing multiple organ, tissue, cellular, and molecular parameters in a whole organism context is a valuable strategy for identifying the mechanism of action of bioactive compounds.

SUBMITTER: Dush MK

PROVIDER: S-EPMC3050558 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Heterotaxin: a TGF-β signaling inhibitor identified in a multi-phenotype profiling screen in Xenopus embryos.

Dush Michael K MK McIver Andrew L AL Parr Meredith A MA Young Douglas D DD Fisher Julie J Newman Donna R DR Sannes Philip L PL Hauck Marlene L ML Deiters Alexander A Nascone-Yoder Nanette N

Chemistry & biology 20110201 2

Disruptions of anatomical left-right asymmetry result in life-threatening heterotaxic birth defects in vital organs. We performed a small molecule screen for left-right asymmetry phenotypes in Xenopus embryos and discovered a pyridine analog, heterotaxin, which disrupts both cardiovascular and digestive organ laterality and inhibits TGF-β-dependent left-right asymmetric gene expression. Heterotaxin analogs also perturb vascular development, melanogenesis, cell migration, and adhesion, and indire ...[more]

PMID: 21338922

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Project description:BackgroundThe emergence of cancer immunotherapies, notably immune checkpoint inhibitors, has revolutionized anti-cancer treatments. These treatments, however, have been reported to be effective in a limited range of cancers and cause immune-related adverse effects. Thus, for a broader applicability and enhanced responsiveness to solid tumor immunotherapy, immunomodulation of the tumor microenvironment is crucial. Transforming growth factor-β (TGF-β) has been implicated in reducing immunotherapy responsiveness by promoting M2-type differentiation of macrophages and facilitating cancer cell metastasis.MethodsIn this study, we developed macrophage membrane-coated nanoparticles loaded with a TGF-βR1 kinase inhibitor, SD-208 (M[Formula: see text]-SDNP). Inhibitions of M2 macrophage polarization and epithelial-to-mesenchymal transition (EMT) of cancer cells were comprehensively evaluated through in vitro and in vivo experiments. Bio-distribution study and in vivo therapeutic effects of M[Formula: see text]-SDNP were investigated in orthotopic breast cancer model and intraveneously injected metastasis model.ResultsM[Formula: see text]-SDNPs effectively inhibited cancer metastasis and converted the immunosuppressive tumor microenvironment (cold tumor) into an immunostimulatory tumor microenvironment (hot tumor), through specific tumor targeting and blockade of M2-type macrophage differentiation. Administration of M[Formula: see text]-SDNPs considerably augmented the population of cytotoxic T lymphocytes (CTLs) in the tumor tissue, thereby significantly enhancing responsiveness to immune checkpoint inhibitors, which demonstrates a robust anti-cancer effect in conjunction with anti-PD-1 antibodies.ConclusionCollectively, responsiveness to immune checkpoint inhibitors was considerably enhanced and a robust anti-cancer effect was demonstrated with the combination treatment of M[Formula: see text]-SDNPs and anti-PD-1 antibody. This suggests a promising direction for future therapeutic strategies, utilizing bio-inspired nanotechnology to improve the efficacy of cancer immunotherapy.

Dataset Information

Heterotaxin: a TGF-? signaling inhibitor identified in a multi-phenotype profiling screen in Xenopus embryos.

Publications

Heterotaxin: a TGF-β signaling inhibitor identified in a multi-phenotype profiling screen in Xenopus embryos.

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