Abstract
The fungus, Mortierella polycephala is one of the most productive sources of anticancer bioactive compounds namely those of pigment nature. During our investigation of the produced bioactive metabolites by the terrestrial M. polycephala AM1 isolated from Egyptian poultry feather waste, two main azaphilonoid pigments, monascin (1) and monascinol (2) were obtained as major products; their structures were identified by 1D (1H&13C) and 2D (1H–1H COSY, HMBC) NMR and HRESI-MS spectroscopic data. Biologically, cytotoxic activities of these compounds were broadly studied compared with the fungal extract. To predict the biological target for the presumed antitumor activity, an in silico study was run toward three proteins, topoisomerase IIα, topoisomerase IIβ, and VEGFR2 kinase. Monascinol (2) was expected to be moderately active against VEGFR2 kinase without any anticipated inhibition toward topo II isoforms. The in vitro study confirmed the docked investigation consistently and introduced monascinol (2) rather than its counterpart (1) as a potent inhibitor to the tested VEGFR2 kinase. Taxonomically, the fungus was identified using morphological and genetic assessments.
Funding source: Lundbeck Foundation
Award Identifier / Grant number: R317-2018-2541
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Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Research funding: This work was partially supported by the Lundbeck Foundation visiting professorship (R317-2018-2541) for M Shaaban.
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Conflict of interest statement: The authors declare that they have no conflict of interest.
References
1. Sawadogo, WR, Schumacher, M, Teiten, M-H, Cerella, C, Dicato, M, Diederich, M. A survey of marine natural compounds and their derivatives with anti-cancer activity reported in 2011. Molecules 2013;18:3641–73. https://doi.org/10.3390/molecules18043641.Search in Google Scholar PubMed PubMed Central
2. WHO. Global status report on noncommunicable diseases 2010; WT 500. Geneva, Switzerland: WHO; 2011.Search in Google Scholar
3. Mangal, M, Sagar, P, Singh, H, Raghava, GP, Agarwal, SM. NPACT: naturally occurring plant-based anti-cancer compound-activity target database. Nucleic Acids Res 2012;41:D1124–9. https://doi.org/10.1093/nar/gks1047.Search in Google Scholar PubMed PubMed Central
4. Elrayess, RA, Gad El-Hak, HN. Anticancer natural products: a review. Cancer Stud Mol Med Open J 2019;5:14–25. https://doi.org/10.17140/csmmoj-5-127.Search in Google Scholar
5. Strobel, G, Daisy, B. Bioprospecting for microbial endophytes and their natural products. Microbiol Mol Biol Rev 2003;67:491–502. https://doi.org/10.1128/mmbr.67.4.491-502.2003.Search in Google Scholar PubMed PubMed Central
6. Xia, Y, Amna, A, Opiyo, SO. The culturable endophytic fungal communities of switchgrass grown on a coalmining site and their effects on plant growth. PloS One 2018;13:1–16. https://doi.org/10.1371/journal.pone.0198994.Search in Google Scholar PubMed PubMed Central
7. Hardoim, PR, van Overbeek, LS, Berg, G, Pirttilä, AM, Compant, S, Campisano, A, et al.. The hidden world within plants: ecological and evolutionary considerations for defining functioning of microbial endophytes. Microbiol Mol Biol Rev 2015;79:293–320. https://doi.org/10.1128/mmbr.00050-14.Search in Google Scholar
8. Kaul, S, Gupta, S, Ahmed, M, Dhar, MK. Endophytic fungi from medicinal plants: a treasure hunt for bioactive metabolites. Phytochemistry Rev 2012;11:487–505. https://doi.org/10.1007/s11101-012-9260-6.Search in Google Scholar
9. Pimentel, MR, Molina, G, Dionisio, AP, Maróstica, MR, Pastore, GM. Use of endophytes to obtain bioactive compounds and their application in biotransformation process. Biotechnol Res Int 2011;2011:576286. https://doi.org/10.4061/2011/576286.Search in Google Scholar PubMed PubMed Central
10. Sarasan, M, Puthumana, J, Job, N, Han, J, Lee, J-S, Philip, R. Marine algicolous endophytic fungi-a promising drug resource of the era. J Microbiol Biotechnol 2017;27:1039–52. https://doi.org/10.4014/jmb.1701.01036.Search in Google Scholar PubMed
11. Akihisa, T, Tokuda, H, Ukiya, M, Kiyota, A, Yasukawa, K, Sakamoto, N, et al.. Antitumor-initiating effects of monascin, an azaphilonoid pigment from the extract of Monascus pilosus fermented rice (red-mold rice). Chem Biodivers 2005;2:1305–9. https://doi.org/10.1002/cbdv.200590101.Search in Google Scholar PubMed
12. Chen, RJ, Hung, CM, Chen, YL, Wu, MD, Yuan, GF, Wang, YJ. Monascuspiloin induces apoptosis and autophagic cell death in human prostate cancer cells via the Akt and AMPK signaling pathways. J Agric Food Chem 2012;60:7185–93. https://doi.org/10.1021/jf3016927.Search in Google Scholar PubMed
13 . Ho-Cheng, W, Hsun-Shuo, C, Ming-Jen, C, Ming-Der, W, Yen-Lin, C, Kai-Ping, C, et al.. Secondary metabolites from the fermented rice of the fungus Monascus purpureus and their bioactivities. Nat Prod Res 2019;33:3541–50.10.1080/14786419.2018.1488698Search in Google Scholar PubMed
14. Li, X, Liu, C, Duan, Z, Guo, S. HMG-CoA reductase inhibitors from monascus-fermented rice. J Chem 2013;2013:1–6. https://doi.org/10.1155/2013/872056.Search in Google Scholar
15. Akihisa, T, Tadashi, Y, Takashi, S, Fukuoka, T. Monascinol and tumor promoter activity inhibitors and food containing it. Patent No. JP2008056618A; 2006.Search in Google Scholar
16. Lin, C-H, Lina, T-H, Pan, T-M. Alleviation of metabolic syndrome by monascin and ankaflavin: the perspective of Monascus functional foods. Food Funct 2017;8:2102–9. https://doi.org/10.1039/c7fo00406k.Search in Google Scholar PubMed
17. Lee, C-L, Wen, J-Y, Hsu, Y-W, Pan, T-M. Monascus-fermented yellow pigments monascin and ankaflavin showed antiobesity effect via the suppression of differentiation and lipogenesis in obese rats fed a high-fat diet. J Agric Food Chem 2013;61:1493–500. https://doi.org/10.1021/jf304015z.Search in Google Scholar PubMed
18. Lee, C-L, Wen, J-Y, Hsu, Y-W, Pan, T-M. Monascin and ankaflavin have more anti-atherosclerosis effect and less side effect involving increasing creatinine phosphokinase activity than monacolin K under the same dosages. J Agric Food Chem 2013;61:143–50. https://doi.org/10.1021/jf304346r.Search in Google Scholar PubMed
19. Hsu, W-H, Chen, T-H, Lee, B-H, Hsu, Y-W, Pan, T-M. Monascin and ankaflavin act as natural AMPK activators with PPARα agonist activity to down-regulate nonalcoholic steatohepatitis in high-fat diet-fed C57BL/6 mice. Food Chem Toxicol 2014;64:94–103. https://doi.org/10.1016/j.fct.2013.11.015.Search in Google Scholar PubMed
20. Nitiss, JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Canc 2009;9:338–50. https://doi.org/10.1038/nrc2607.Search in Google Scholar PubMed PubMed Central
21. Lian, L, Li, X-L, Xu, M-D, Li, X-M, Wu, M-Y, Zhang, Y, et al.. VEGFR2 promotes tumorigenesis and metastasis in a pro-angiogenic-independent way in gastric cancer. BMC Canc 2019;19:183. https://doi.org/10.1186/s12885-019-5322-0.Search in Google Scholar PubMed PubMed Central
22. RCSB protein data bank-RCSB PDB. Available from: http://www.rcsb.org/pdb/home/home.do.Search in Google Scholar
23. Trott, O, Olson, AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010;31:455–61. https://doi.org/10.1002/jcc.21334.Search in Google Scholar PubMed PubMed Central
24. Classen, S, Olland, S, Berger, JM. Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187. Proc Natl Acad Sci U S A 2003;100:10629–34. https://doi.org/10.1073/pnas.1832879100.Search in Google Scholar PubMed PubMed Central
25. Pastor, N, Domínguez, I, Orta, ML, Campanella, C, Mateos, S, Cortés, F. The DNA topoisomerase II catalytic inhibitor merbarone is genotoxic and induces endoreduplication. Mutat Res Fund Mol Mech Mutagen 2012;738–739:45–51. https://doi.org/10.1016/j.mrfmmm.2012.07.005.Search in Google Scholar PubMed
26. Skok, Ž, Zidar, N, Kikelj, D, Ilaš, J. Dual inhibitors of human DNA topoisomerase II and other cancer-related targets. J Med Chem 2020;63:884–904. https://doi.org/10.1021/acs.jmedchem.9b00726.Search in Google Scholar PubMed
27. Fisher, FW, Cook, NB. Fundamentals of diagnostic mycology. Philadelphia, PA: Saunders; 1998.Search in Google Scholar
28. Martin, BE, Pamela, JE. Microfungi on land plants, an identification handbook. New England: Richmond Publishing; 1985.Search in Google Scholar
29. Orgensen, JH, Turnidge, JD. Susceptibility test methods: dilution and disk diffusion methods. In: Murray, PR, Baron, EJ, Jorgensen, JH, Landry, ML, Pfaller, MA, editors. Manual of clinical microbiology, 9th ed. Washington, D.C: ASM Press; 2007:1152–72 pp.10.1128/9781555817381.ch71Search in Google Scholar
b) Sajid, I, Fondja, YCB, Shaaban, KA, Hasnain, S, Laatsch, H. Antifungal and antibacterial activities of indigenous Streptomyces isolates from saline farmlands: prescreening, ribotyping and metabolic diversity. World J Microbiol Biotechnol 2009;25:601–10. https://doi.org/10.1007/s11274-008-9928-7.Search in Google Scholar
30. Pedretti, A, Villa, L, Vistoli, G. Atom-type description language: a universal language to recognize atom types implemented in the VEGA program. Theor Chem Acc 2003;109:229–32. https://doi.org/10.1007/s00214-002-0402-6.Search in Google Scholar
31. Morris, GM, Huey, R, Lindstrom, W, Sanner, MF, Belew, RK, Goodsell, DS, et al.. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785–91. https://doi.org/10.1002/jcc.21256.Search in Google Scholar PubMed PubMed Central
32. Schrodinger. The PyMOL molecular graphics system. Version 1.8 Schrödinger, LLC; 2015.Search in Google Scholar
33. Wei, H, Ruthenburg, AJ, Bechis, SK, Verdine, GL. Nucleotide-dependent domain movement in the ATPase domain of a human type IIA DNA topoisomerase. J Biol Chem 2005;280:37041–7. https://doi.org/10.1074/jbc.m506520200.Search in Google Scholar PubMed
34. Wu, C-C, Li, T-K, Farh, L, Lin, L-Y, Lin, T-S, Yu, Y-J, et al.. Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science 2011;333:459–62. https://doi.org/10.1126/science.1204117.Search in Google Scholar PubMed
35. Oguro, Y, Miyamoto, N, Okada, K, Takagi, T, Iwata, H, Awazu, Y, et al.. Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-Pyrrolo[3,2-d]Pyrimidine derivatives: novel VEGFR2 kinase inhibitors binding to inactive kinase conformation. Bioorg Med Chem 2010;18:7260–73. https://doi.org/10.1016/j.bmc.2010.08.017.Search in Google Scholar PubMed
Supplementary material
The online version of this article offers supplementary material (https://doi.org/10.1515/znc-2021-0095).
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