Discovery and characterization of Isofistularin-3, a marine brominated alkaloid, as a new DNA demethylating agent inducing cell cycle arrest and sensitization to TRAIL in cancer cells
- PMID: 27006469
- PMCID: PMC5029682
- DOI: 10.18632/oncotarget.8210
Discovery and characterization of Isofistularin-3, a marine brominated alkaloid, as a new DNA demethylating agent inducing cell cycle arrest and sensitization to TRAIL in cancer cells
Abstract
We characterized the brominated alkaloid Isofistularin-3 (Iso-3), from the marine sponge Aplysina aerophoba, as a new DNA methyltransferase (DNMT)1 inhibitor. Docking analysis confirmed our in vitro DNMT inhibition data and revealed binding of Iso-3 within the DNA binding site of DNMT1. Subsequent increased expression of tumor suppressor gene aryl hydrocarbon receptor (AHR) could be correlated to decreased methylation of CpG sites within the essential Sp1 regulatory region of its promoter. Iso-3 induced growth arrest of cancer cells in G0/G1 concomitant with increased p21 and p27 expression and reduced cyclin E1, PCNA and c-myc levels. Reduced proliferation was accompanied by morphological changes typical of autophagy revealed by fluorescent and transmission electron microscopy and validated by LC3I-II conversion. Furthermore, Iso-3 strongly synergized with tumor-necrosis-factor related apoptosis inducing ligand (TRAIL) in RAJI [combination index (CI) = 0.22] and U-937 cells (CI = 0.21) and increased TRAIL-induced apoptosis via a mechanism involving reduction of survivin expression but not of Bcl-2 family proteins nor X-linked inhibitor of apoptosis protein (XIAP). Iso-3 treatment decreased FLIPL expression and triggered activation of endoplasmatic reticulum (ER) stress with increased GRP78 expression, eventually inducing TRAIL receptor death receptor (DR)5 surface expression. Importantly, as a potential candidate for further anticancer drug development, Iso-3 reduced the viability, colony and in vivo tumor forming potential without affecting the viability of PBMCs from healthy donors or zebrafish development.
Keywords: DNMT inhibitor; TSG hypermethylation; autophagy; cell cycle arrest; leukemia.
Conflict of interest statement
The authors declare no conflicts of interest.
Figures
Similar articles
-
Metformin Causes G1-Phase Arrest via Down-Regulation of MiR-221 and Enhances TRAIL Sensitivity through DR5 Up-Regulation in Pancreatic Cancer Cells.PLoS One. 2015 May 8;10(5):e0125779. doi: 10.1371/journal.pone.0125779. eCollection 2015. PLoS One. 2015. PMID: 25955843 Free PMC article.
-
Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction.Cancer Res. 2005 Dec 15;65(24):11469-77. doi: 10.1158/0008-5472.CAN-05-1724. Cancer Res. 2005. PMID: 16357155
-
Insulin promotes vascular smooth muscle cell proliferation and apoptosis via differential regulation of tumor necrosis factor-related apoptosis-inducing ligand.J Diabetes. 2016 Jul;8(4):568-78. doi: 10.1111/1753-0407.12339. Epub 2015 Dec 7. J Diabetes. 2016. PMID: 26333348
-
TRAIL as a target in anti-cancer therapy.Cancer Lett. 2009 Nov 18;285(1):1-5. doi: 10.1016/j.canlet.2009.02.029. Epub 2009 Mar 18. Cancer Lett. 2009. PMID: 19299078 Review.
-
Spatial dynamics of TRAIL death receptors in cancer cells.Drug Resist Updat. 2015 Mar;19:13-21. doi: 10.1016/j.drup.2015.02.001. Epub 2015 Mar 9. Drug Resist Updat. 2015. PMID: 25840763 Review.
Cited by
-
Epigenetic Regulation of TRAIL Signaling: Implication for Cancer Therapy.Cancers (Basel). 2019 Jun 19;11(6):850. doi: 10.3390/cancers11060850. Cancers (Basel). 2019. PMID: 31248188 Free PMC article. Review.
-
Bioactive Bromotyrosine-Derived Alkaloids from the Polynesian Sponge Suberea ianthelliformis.Mar Drugs. 2018 Apr 27;16(5):146. doi: 10.3390/md16050146. Mar Drugs. 2018. PMID: 29702602 Free PMC article.
-
Marine-Derived Secondary Metabolites as Promising Epigenetic Bio-Compounds for Anticancer Therapy.Mar Drugs. 2020 Dec 31;19(1):15. doi: 10.3390/md19010015. Mar Drugs. 2020. PMID: 33396307 Free PMC article. Review.
-
Marine Actinomycetes-Derived Secondary Metabolites Overcome TRAIL-Resistance via the Intrinsic Pathway through Downregulation of Survivin and XIAP.Cells. 2020 Jul 22;9(8):1760. doi: 10.3390/cells9081760. Cells. 2020. PMID: 32708048 Free PMC article.
-
Targeting one-carbon metabolism for cancer immunotherapy.Clin Transl Med. 2024 Jan;14(1):e1521. doi: 10.1002/ctm2.1521. Clin Transl Med. 2024. PMID: 38279895 Free PMC article. Review.
References
-
- Schnekenburger M, Florean C, Dicato M, Diederich M. Epigenetic alterations as a universal feature of cancer hallmarks and a promising target for personalized treatments. Curr Top Med Chem. 2016;16:745–776. - PubMed
-
- Florean C, Schnekenburger M, Grandjenette C, Dicato M, Diederich M. Epigenomics of leukemia: from mechanisms to therapeutic applications. Epigenomics. 2011;3:581–609. - PubMed
-
- Seidel C, Florean C, Schnekenburger M, Dicato M, Diederich M. Chromatin-modifying agents in anti-cancer therapy. Biochimie. 2012;94:2264–2279. - PubMed
-
- Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov. 2006;5:37–50. - PubMed
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous
