Abstract
Citreamicin epsilon is a group of antitumor compounds produced by Streptomyces species. Cytotoxicology study of two diastereomers, citreamicin epsilon A and B, showed different apoptotic effects on PtK2 cells with IC50 (half-maximal inhibitory concentration) values of 0.086 and 0.025 mu M, respectively. Thus, we performed an iTRAQ (isobaric tags for relative and absolute quantitation)-based quantitative proteomic analysis to reveal the mechanism of cytotoxicity of citreamicin epsilon A and B in PtK2 cells. A total of 1,079 proteins were identified and quantified, among which 103 and 94 proteins displayed significant changes in expression levels after the treatment of citreamicin epsilon A and B, respectively. These significantly differentially expressed proteins (DEPs) were further annotated by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction analysis, which revealed the involvement of eight molecular pathways. Among them, expression trends of proteins involved in the nuclear transcription factor kappa B (NF-kappa B) pathway displayed the opposite between the two diastereomer treatments, indicating different modes of action of these two compounds. Citreamicin epsilon A treatment induced rapid activation of the NF-kappa B pathway, which might promote cell survival and resulted in lower toxicity. Our comparative proteomic analysis provided molecular evidence on the toxicity of two diastereomers compounds to cells, which may shed new light on future mechanism study of these antitumor compounds.
Highlights
Marine natural products play an important role in modern drug development (Gerwick and Moore, 2012; Khalifa et al, 2019)
To determine whether the cytotoxic effect caused by citreamicin ε A and B was related to apoptosis, we performed a TUNEL assay that detected cells undergoing DNA fragmentation
Compared with the cells treated with dimethyl sulfoxide (DMSO), TUNEL-positive cells could be observed in the treatment of citreamicin ε A and B (Supplementary Figure S1)
Summary
Marine natural products play an important role in modern drug development (Gerwick and Moore, 2012; Khalifa et al, 2019). Citreamicins that are a group of polyketide compounds produced by Streptomyces species have been patented as potential candidates for anticancer drug discovery (Peoples et al, 2009). Most of the citreamicins displayed inhibitory activity against the Grampositive bacteria, including multidrug-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis (Carter et al, 1990; Qadri et al, 1992; Peoples et al, 2008). The potent biological activity and the structural complexity of citreamicins captured the attention of the chemical synthesis study (Blumberg and Martin, 2017, 2018). Citreamicin ε as one of the most potent members of the family possessed a basic chemical structure of seven condensed rings, including six polycyclic aromatic rings and an oxazolidone ring with two chiral centers. The previous bioactivity study of the citreamicins was almost based on the optical mixture compounds (Hopp et al, 2008)
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