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.
Highlights
Cancer represents the second leading cause of death worldwide, and its incidence and mortality are growing [1]
Tumor cell viability was determined after 48 h treatment by MTT assay, leading to IC50 values in the nano to low micromolar range (Table 1, Figure S1A)
Due to the discrepancy between the cytotoxicity expected based on MTT results and that confirmed by apoptotic and necrotic events as well as the fact that the MTT assay is a metabolic assay, we suggested an influence of Thioholgamide A (thioA) treatment on metabolism
Summary
Cancer represents the second leading cause of death worldwide, and its incidence and mortality are growing [1]. Increasing evidence indicates that the tumor microenvironment (TME) contributes to the acquisition of hallmarks of cancer traits. These comprise, e.g., sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling metastasis, reprogramming of energy metabolism, and evading immune destruction [5]. Innate immune cells are highly represented in the TME, with tumor-associated macrophages (TAMs) being the major population [7]. The macrophage population is predominantly skewed towards an M2-like phenotype [8]. This polarization state orchestrates cancer-related inflammation, supports angiogenesis, extracellular matrix remodeling, and tumor cell proliferation. Thereby macrophages promote tumor growth and metastasis [9,10]
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