Tetracenomycin Aglycones Primarily Inhibit Cell Growth and Proliferation in Mammalian Cancer Cell Lines
Source abstract
Abstract
Tetracenomycins are anticancer polyketides that arrest cancer cell proliferation via binding to the large mammalian ribosomal subunit near the polypeptide exit channel. The tetracenomycins are natural products that many members of the actinomycete family produce. The first goal of this study was to improve the biosynthesis of tetracenomycin analogs via metabolic engineering. The second goal was to probe more deeply into the antiproliferative activity of tetracenomycin aglycones. The tetracenomycins were assessed via several assays, including cell viability assays, clonogenic assays, and flow cytometry apoptosis assays. The data suggest that tetracenomycins C and X inhibit cell proliferation and arrest cell growth, supporting their cytostatic action mechanism. In addition, tetracenomycins C and X induced degeneration of 3D spheroid cultures and exhibited concentration-dependent inhibition of cell survival and colony formation in clonogenic assays. This work demonstrates that tetracenomycins act mainly as cytostatic rather than apoptotic agents.
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Research context
OpenAlex topics: Microbial Natural Products and Biosynthesis · Cancer therapeutics and mechanisms · Peptidase Inhibition and Analysis
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Pharmaceutical Sciences, College of Pharmacy, Ferris State University, Big Rapids, MI 49307, USA
Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
Funding
National Cancer Institute of the National Institutes of Health · National Science Foundation · National Institutes of Health · Center of Biomedical Research Excellence (COBRE) for Translational Chemical Biology · National Institute of Food and Agriculture · University of Kentucky College of Pharmacy
References (42)
Show source-provided references
1. Stoffwechselprodukte von Mikroorganismen. 175. Mitteilung. Tetracenomycin C10.1007/BF00689973 ↗
2. The Structure of Tetracenomycin C10.7164/antibiotics.45.1190 ↗
3. Structure-Activity Relationships of Elloramycin and Tetracenomycin C10.7164/antibiotics.43.1169 ↗
4. Elloramycins B, C, D, E and F: Minor Congeners of the Elloramycin Producer Streptomyces Olivaceus10.7164/antibiotics.39.856 ↗
5. Metabolic Products of Microorganisms. 225 Elloramycin, a New Anthracycline-like Antibiotic from Streptomyces Olivaceus Isolation, Characterization, Structure and Biological Properties10.7164/antibiotics.38.1291 ↗
6. Isolation of Tetracenomycin C-Nonproducing Streptomyces Glaucescens Mutants10.1128/jb.167.2.575-580.1986 ↗
7. Identification of a Sugar Flexible Glycosyltransferase from Streptomyces Olivaceus, the Producer of the Antitumor Polyketide Elloramycin10.1016/S1074-5521(01)00010-2 ↗
8. Cloning and Characterization of a Polyketide Synthase Gene from Streptomyces Fradiae Tü2717, Which Carries the Genes for Biosynthesis of the Angucycline Antibiotic Urdamycin A and a Gene Probably Involved in Its Oxygenation10.1128/jb.177.21.6126-6136.1995 ↗
9. Tetracenomycin X Inhibits Translation by Binding within the Ribosomal Exit Tunnel10.1038/s41589-020-0578-x ↗
10. Tetracenomycin X Sequesters Peptidyl-TRNA during Translation of QK Motifs10.1038/s41589-023-01343-0 ↗
11. Engineering BioBricks for Deoxysugar Biosynthesis and Generation of New Tetracenomycins10.1021/acsomega.3c02460 ↗
12. Sambrook, J., and Russell, D.W. (2001). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press.
13. Analysis of Streptomyces Avermitilis Genes Required for Avermectin Biosynthesis Utilizing a Novel Integration Vector10.1016/0378-1119(92)90603-M ↗
14. Kieser, T., Bibb, M.J., Buttner, M.J., Chater, K.F., and Hopwood, D.A. (2000). Practical Streptomyces Genetics, John Innes Centre Ltd.
15. Ketoolivosyl-Tetracenomycin C: A New Ketosugar Bearing Tetracenomycin Reveals New Insight into the Substrate Flexibility of Glycosyltransferase ElmGT10.1016/j.bmcl.2012.01.094 ↗
16. Nguyen, J.T., Riebschleger, K.K., Brown, K.V., Gorgijevska, N.M., and Nybo, S.E. (2022). A BioBricks Toolbox for Metabolic Engineering of the Tetracenomycin Pathway. Biotechnol. J., 17.10.1002/biot.202100371 ↗
17. Intergeneric Conjugation between Escherichia Coli and Streptomyces Species10.1128/jb.171.6.3583-3585.1989 ↗
18. Poku, R.A., Jones, K.J., Van Baren, M., Alan, J.K., and Amissah, F. (2020). Diclofenac Enhances Docosahexaenoic Acid-Induced Apoptosis in Vitro in Lung Cancer Cells. Cancers, 12.10.3390/cancers12092683 ↗
19. PI3K Functions Downstream of Cdc42 to Drive Cancer Phenotypes in a Melanoma Cell Line10.1080/21541248.2023.2202612 ↗
20. Spheroid-Based Drug Screen: Considerations and Practical Approach10.1038/nprot.2008.226 ↗
21. Qiao, X., Gan, M., Wang, C., Liu, B., Shang, Y., Li, Y., and Chen, S. (2019). Tetracenomycin X Exerts Antitumour Activity in Lung Cancer Cells through the Downregulation of Cyclin D1. Mar. Drugs, 17.10.3390/md17010063 ↗
22. A Mechanistic Investigation on the Anticancer Properties of SYA013, a Homopiperazine Analogue of Haloperidol with Activity against Triple Negative Breast Cancer Cells10.1021/acsomega.0c03495 ↗
23. Wong, F.T., and Khosla, C. (2012). Combinatorial Biosynthesis of Polyketides—A Perspective. Curr. Opin. Chem. Biol., 16.10.1016/j.cbpa.2012.01.018 ↗
24. Modelling the Morphology of Filamentous Microorganisms10.1016/0167-7799(96)10055-X ↗
25. Production of Poly-β-1,6-N-Acetylglucosamine by MatAB Is Required for Hyphal Aggregation and Hydrophilic Surface Adhesion by Streptomyces10.15698/mic2018.06.635 ↗
26. Unlocking Streptomyces Spp. for Use as Sustainable Industrial Production Platforms by Morphological Engineering10.1128/AEM.00808-06 ↗
27. SsgA-like Proteins Determine the Fate of Peptidoglycan during Sporulation of Streptomyces Coelicolor10.1111/j.1365-2958.2005.04883.x ↗
28. Li, X., Wang, J., Li, S., Ji, J., Wang, W., and Yang, K. (2015). ScbR-and ScbR2-Mediated Signal Transduction Networks Coordinate Complex Physiological Responses in Streptomyces Coelicolor. Sci. Rep., 5.10.1038/srep14831 ↗
29. A Novel Locus for Mycelial Aggregation Forms a Gateway to Improved Streptomyces Cell Factories10.1186/s12934-015-0224-6 ↗
30. New Approaches to Achieve High Level Enzyme Production in Streptomyces Lividans10.1186/s12934-016-0425-7 ↗
31. “Pseudo” γ-Butyrolactone Receptors Respond to Antibiotic Signals to Coordinate Antibiotic Biosynthesis10.1074/jbc.M110.143081 ↗
32. Angucyclines as Signals Modulate the Behaviors of Streptomyces Coelicolor10.1073/pnas.1324253111 ↗
33. Engineering Streptomyces Coelicolor for Heterologous Expression of Secondary Metabolite Gene Clusters10.1111/j.1751-7915.2010.00219.x ↗
34. Enzyme-Constrained Models and Omics Analysis of Streptomyces Coelicolor Reveal Metabolic Changes That Enhance Heterologous Production10.1016/j.isci.2020.101525 ↗
35. Kumelj, T.S., Sulheim, S., Wentzel, A., and Almaas, E. (2019). Predicting Strain Engineering Strategies Using IKS1317: A Genome-Scale Metabolic Model of Streptomyces Coelicolor. Biotechnol. J., 14.10.1002/biot.201800180 ↗
36. Engineering of Primary Carbohydrate Metabolism for Increased Production of Actinorhodin in Streptomyces Codicolor10.1128/AEM.01308-06 ↗
37. Liu, B., Li, J., Chen, M., Hao, X., Cao, F., Tan, Y., Ping, Y., Wang, Y., Xiao, C., and Gan, M. (2018). Seco-Tetracenomycins from the Marine-Derived Actinomycete Saccharothrix Sp. 10-10. Mar. Drugs, 16.10.3390/md16100345 ↗
38. Saccharothrixones A-D, Tetracenomycin-Type Polyketides from the Marine-Derived Actinomycete Saccharothrix Sp. 10-1010.1021/acs.jnatprod.5b00577 ↗
39. Diverse Combinatorial Biosynthesis Strategies for C–H Functionalization of Anthracyclinones10.1021/acssynbio.4c00043 ↗
40. A BioBricks Metabolic Engineering Platform for the Biosynthesis of Anthracyclinones in Streptomyces Coelicolor10.1021/acssynbio.2c00498 ↗
41. Aubry, C., Pernodet, J.L., and Lautru, S. (2019). Modular and integrative vectors for synthetic biology applications in Streptomyces spp. Appl. Environ. Microbiol., 85.10.1128/AEM.00485-19 ↗
42. High efficiency intergeneric conjugal transfer of plasmid DNA from Escherichia coli to methyl DNA-restricting Streptomycetes10.1111/j.1574-6968.1997.tb13882.x ↗