Induction of mitochondria-mediated apoptosis and suppression of tumor growth in zebrafish xenograft model by cyclic dipeptides identified from Exiguobacterium acetylicum

• Published in: Scientific reports Vol. 10; no. 1; p. 13721
• Main Authors: Jinendiran, Sekar, Teng, Weilin, Dahms, Hans-Uwe, Liu, Wangta, Ponnusamy, Vinoth Kumar, Chiu, Charles Chien-Chih, Kumar, B. S. Dileep, Sivakumar, Natesan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.08.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326; 631/337; 631/67; 692/4017; 692/53; Acetic acid; Animals; Apoptosis; Bcl-2 protein; Cancer; Caspase-3; Cell death; Cell Proliferation; Cell viability; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Cyclic dipeptides; Cytochrome c; Cytotoxicity; Danio rerio; Dipeptides - pharmacology; Ethyl acetate; Exiguobacterium; Exiguobacterium - chemistry; Humanities and Social Sciences; Humans; Mitochondria; Mitochondria - metabolism; multidisciplinary; Peptides, Cyclic - pharmacology; Science; Science (multidisciplinary); Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Xenografts; Zebrafish
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-70516-x

Colorectal cancer is the most common type of gastrointestinal cancers with poor survival and limited therapeutic options. In this study, four structurally different cyclic dipeptides (or diketopiperazine) were isolated and identified as cyclo ( l -Pro- l -Leu), cyclo ( l -Pro- l -Val), cyclo ( l -Pro- l -Phe) and cyclo ( l -Pro- l -Tyr) from the ethyl acetate extract in the cell-free filtrate of Exiguobacterium acetylicum S01. The anticancer potential of identified DKPs on colorectal cancer HT-29 cells in vitro and in vivo zebrafish xenograft model was evaluated. The MTT (3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide)) assay showed that four DKPs exhibited significant inhibition of HT-29 cells viability in a dose-dependent manner whereas there were no cytotoxic effects on normal mouse fibroblast 3T3 cells. Also, we observed that all DKPs induce early and late apoptotic cell death in HT-29 cells. Moreover, the expression levels of apoptotic (cytochrome-c, caspase-3 and Bid) and anti-apoptotic (Bcl-2) markers were up- and down-regulated in HT-29 cells in response to DKPs treatments. Furthermore, these four DKPs remarkably inhibited the tumor progression in a zebrafish xenograft model within a nonlethal dose range. Overall, our findings suggest that cyclic dipeptides derived from E. acetylicum S01 could be promising chemopreventive/ therapeutic candidates against cancer.