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

被引：29

作者：

Dahlem, Charlotte ^{[1
]}

Siow, Wei Xiong ^{[2
]}

Lopatniuk, Maria ^{[3
]}

Tse, William K. F. ^{[4
]}

Kessler, Sonja M. ^{[1
,5
]}

Kirsch, Susanne H. ^{[6
]}

Hoppstaedter, Jessica ^{[1
]}

Vollmar, Angelika M. ^{[2
]}

Mueller, Rolf ^{[6
,7
]}

Luzhetskyy, Andriy ^{[3
,6
]}

Bartel, Karin ^{[2
]}

Kiemer, Alexandra K. ^{[1
]}

机构：

[1] Saarland Univ, Pharmaceut Biol, Dept Pharm, Campus C2 3, D-66123 Saarbrucken, Germany

[2] Ludwig Maximilians Univ Munchen, Dept Pharm, Pharmaceut Biol, Butenandtstr 5-13, D-81377 Munich, Germany

[3] Saarland Univ, Pharmaceut Biotechnol, Dept Pharm, Campus C2 3, D-66123 Saarbrucken, Germany

[4] Kyushu Univ, Fac Agr, Ctr Promot Int Educ & Res, Nishi Ku, 744 Motooka, Fukuoka, Fukuoka 8190395, Japan

[5] Martin Luther Univ Halle Wittenberg, Dept Pharmacol Nat Sci, Inst Pharm, D-06120 Halle, Germany

[6] Helmholtz Ctr Infect Res, Helmholtz Inst Pharmaceut Res Saarland HIPS, Dept Microbial Nat Prod, Campus E8 1, D-66123 Saarbrucken, Germany

[7] Saarland Univ, Dept Pharm, D-66123 Saarbrucken, Germany

来源：

CANCERS | 2020年 / 12卷 / 05期

关键词：

RiPPs; OXPHOS; M2; macrophages; TAM-like macrophages; phagocytosis; thioviridamide-like compounds; scratch assay; mitochondria; migration; qPCR; flow cytometry; HUVEC; TUMOR-ASSOCIATED MACROPHAGES; CANCER; CELL; PHAGOCYTOSIS; APOPTOSIS; PHENOTYPE;

D O I：

10.3390/cancers12051288

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：21

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