TY - JOUR
T1 - Thioholgamide a, a new anti-proliferative anti-tumor agent, modulates macrophage polarization and metabolism
AU - Dahlem, Charlotte
AU - Siow, Wei Xiong
AU - Lopatniuk, Maria
AU - Tse, William K.F.
AU - Kessler, Sonja M.
AU - Kirsch, Susanne H.
AU - Hoppstädter, Jessica
AU - Vollmar, Angelika M.
AU - Müller, Rolf
AU - Luzhetskyy, Andriy
AU - Bartel, Karin
AU - Kiemer, Alexandra K.
N1 - Funding Information:
Acknowledgments: Core Facility “Analyse“ Agilent Seahorse XFe96 Analyser, University Hospital Halle (Saale), Martin Luther University Halle-Wittenberg, and Samiya Al-Robaiy for the assistance during the Seahorse measurements; Julia Wildfeuer for her assistance in compound purification and viability measurements. We acknowledge support by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and Saarland University within the funding programme Open Access Publishing.
Funding Information:
This research was funded by Landesforschungsförderung, grant number LFFP 17/08, and Deutsche Forschungsgemeinschaft, grant number KI702. Core Facility “Analyse“ Agilent Seahorse XFe96 Analyser, University Hospital Halle (Saale), Martin Luther University Halle-Wittenberg, and Samiya Al-Robaiy for the assistance during the Seahorse measurements; Julia Wildfeuer for her assistance in compound purification and viability measurements. We acknowledge support by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and Saarland University within the funding programme Open Access Publishing.
Funding Information:
Funding: This research was funded by Landesforschungsförderung, grant number LFFP 17/08, and Deutsche Forschungsgemeinschaft, grant number KI702.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
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U2 - 10.3390/cancers12051288
DO - 10.3390/cancers12051288
M3 - Article
AN - SCOPUS:85085377417
SN - 2072-6694
VL - 12
JO - Cancers
JF - Cancers
IS - 5
M1 - 1288
ER -
