Thioholgamide a, a new anti-proliferative anti-tumor agent, modulates macrophage polarization and metabolism

Charlotte Dahlem, Wei Xiong Siow, Maria Lopatniuk, William K.F. Tse, Sonja M. Kessler, Susanne H. Kirsch, Jessica Hoppstädter, Angelika M. Vollmar, Rolf Müller, Andriy Luzhetskyy, Karin Bartel, Alexandra K. Kiemer

Research output: Contribution to journalArticle

Abstract

Natural products represent powerful tools searching for novel anticancer drugs. Thioholgamide A (thioA) is a ribosomally synthesized and post-translationally modified peptide, which has been identified as a product of Streptomyces sp. MUSC 136T. In this study, we provide a comprehensive biological profile of thioA, elucidating its effects on different hallmarks of cancer in tumor cells as well as in macrophages as crucial players of the tumor microenvironment. In 2D and 3D in vitro cell culture models thioA showed potent anti-proliferative activities in cancer cells at nanomolar concentrations. Anti-proliferative actions were confirmed in vivo in zebrafish embryos. Cytotoxicity was only induced at several-fold higher concentrations, as assessed by live-cell microscopy and biochemical analyses. ThioA exhibited a potent modulation of cell metabolism by inhibiting oxidative phosphorylation, as determined in a live-cell metabolic assay platform. The metabolic modulation caused a repolarization of in vitro differentiated and polarized tumor-promoting human monocyte-derived macrophages: ThioA-treated macrophages showed an altered morphology and a modulated expression of genes and surface markers. Taken together, the metabolic regulator thioA revealed low activities in non-tumorigenic cells and an interesting anti-cancer profile by orchestrating different hallmarks of cancer, both in tumor cells as well as in macrophages as part of the tumor microenvironment.

Original languageEnglish
Article number1288
JournalCancers
Volume12
Issue number5
DOIs
Publication statusPublished - May 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Dahlem, C., Siow, W. X., Lopatniuk, M., Tse, W. K. F., Kessler, S. M., Kirsch, S. H., Hoppstädter, J., Vollmar, A. M., Müller, R., Luzhetskyy, A., Bartel, K., & Kiemer, A. K. (2020). Thioholgamide a, a new anti-proliferative anti-tumor agent, modulates macrophage polarization and metabolism. Cancers, 12(5), [1288]. https://doi.org/10.3390/cancers12051288