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5. Thioholgamide A, a New Anti-Proliferative Anti-Tumor Agent, Modulates Macrophage Polarization and Metabolism.

Author

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

Subjects
*CELL proliferation, *ANIMAL experimentation, *ANTIGENS, *ANTINEOPLASTIC agents, *BIOCHEMISTRY, *BIOLOGICAL models, *CELL physiology, *ENERGY metabolism, *FISHES, *FLOW cytometry, *GENE expression, *GRAM-positive bacteria, *MACROPHAGES, *MICROSCOPY, *MITOCHONDRIA, *PEPTIDES, *PHAGOCYTOSIS, *POLYMERASE chain reaction, *PHENOTYPES, *EMBRYOS, *CANCER cell culture, *IN vitro studies, *IN vivo studies, *PHARMACODYNAMICS
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. [ABSTRACT FROM AUTHOR]

Published
2020
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