Abstract
Thioalbamide, a thioamidated peptide biosynthesized by Amycolatopsis alba, is a thioviridamide-like molecule, and is part of a family of natural products representing a focus of biotechnological and pharmaceutical research in recent years due to their potent anti-proliferative and cytotoxic activities on malignant cells. Despite the high antitumor potential observed at nanomolar concentrations, the mechanisms underlying thioalbamide activity are still not known. In this work, the cellular effects induced by thioalbamide treatment on breast cancer cell lines were evaluated for the first time, highlighting the ability of this microbial natural peptide to induce mitochondrial dysfunction, oxidative stress, and apoptotic cell death. Furthermore, we demonstrate that thioalbamide can inhibit the propagation of cancer stem-like cells, which are strongly dependent on mitochondrial function and are responsible for chemotherapy resistance, metastasis, and tumor recurrence.
Highlights
Thioalbamide (Figure 1), a recently identified natural product [1], is biosynthesized by Amycolatopsis alba DSM 44262, and belongs to the family of ribosomally synthesized and post-translationally modified peptides (RiPPs)
The antiproliferative effects of thioalbamide were evaluated over a wide range of breast cancer cell lines characterized by differences in the status of the three main receptors conventionally used for breast cancer subtyping: estrogen receptor (ER), progesterone receptor (PR), and human epithelial receptor 2 (HER2) [17]
The results obtained indicate that thioalbamide is able to reduce, in a dose-dependent manner, mammosphere formation efficiency in all the cell lines tested (Figure 7a,b) as well as the aldehyde dehydrogenase (ALDH)+ population in MCF7-derived spheroids (Figure 7c) and CD 44 expression in adherent cells and mammospheres (Figure 7d and Figure S10). These results demonstrate a significant inhibition of breast cancer stem cells, confirming thioalbamide inhibitory effects on cell metabolism and opening new scenarios regarding the use of this natural product in the oncologic field
Summary
Thioalbamide (Figure 1), a recently identified natural product [1], is biosynthesized by Amycolatopsis alba DSM 44262, and belongs to the family of ribosomally synthesized and post-translationally modified peptides (RiPPs). This class of natural products is generated by a series of post-translational modifications occurring to a precursor peptide by the action of pathway-specific enzymes, which are encoded in a gene cluster [2]. CSCs are a subset of cancer cells that are highly resistant to current therapeutic strategies, and are believed responsible for tumor recurrence and metastasis [10] In this context, thioalbamide is revealed to be a promising natural agent that is able to affect tumorigenicity
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