Molecular nutrition & food research, 2018-09, Vol.62 (18), p.e1800228-n/a
2018
Details
- Autor(en) / Beteiligte
- Titel
- Heterocyclic Analogs of Sulforaphane Trigger DNA Damage and Impede DNA Repair in Colon Cancer Cells: Interplay of HATs and HDACs
- Ist Teil von
- Molecular nutrition & food research, 2018-09, Vol.62 (18), p.e1800228-n/a
- Ort / Verlag
- Germany: Wiley Subscription Services, Inc
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- Wiley Online Library - AutoHoldings Journals
- Beschreibungen/Notizen
- Scope DNA repair inhibitors have broad clinical applications in tumor types with DNA repair defects, including colorectal cancer (CRC). Structural analogs of the anticancer agent sulforaphane (SFN) were investigated as modifiers of histone deacetylase (HDAC) and histone acetyltransferase (HAT) activity, and for effects on DNA damage/repair pertinent to human CRC. Methods and results In the polyposis in rat colon (Pirc) model, single oral administration of SFN and structurally related long‐chain isothiocyanates (ITCs) decreased histone deacetylase 3 (HDAC3) expression and increased pH2AX levels markedly in adenomatous colon polyps, extending prior observations on HDAC3 inhibition/turnover in cell‐based assays. Colon cancer cells at a high initial plating density had diminished cytotoxicity from SFN, whereas novel tetrazole‐containing heterocyclic analogs of SFN retained their efficacy. The potent SFN analogs triggered DNA damage, cell cycle arrest, apoptosis, and loss of a key DNA repair regulator, C‐terminal binding protein (CtBP) interacting protein (CtIP). These SFN analogs also altered HAT/HDAC activities and histone acetylation status, lowered the expression of HDAC3, P300/CBP‐associated factor (PCAF) and lysine acetyltransferase 2A (KAT2A/GCN5), and attenuated homologous recombination (HR)/non‐homologous end joining (NHEJ) repair activities in colon cancer cells. Conclusion Novel tetrazole‐containing heterocyclic analogs of SFN provide a new avenue for chemosensitization in colon cancer cells via modulation of HAT/HDAC activities and associated DNA damage/repair signaling pathways. DNA repair inhibitors have broad clinical applications in malignancies characterized by DNA repair defects, including colorectal cancer (CRC). Novel, potent tetrazole‐containing analogs of the anticancer agent sulforaphane (SFN) modify histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities, and dysregulate DNA repair pathways in human colon cancer cells, leading to cell death.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1613-4125eISSN: 1613-4133DOI: 10.1002/mnfr.201800228Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6553464
- Format
- –
- Schlagworte
- Acetylation, Analogs, Animals, Anticancer properties, Apoptosis, Apoptosis - drug effects, Brassica - chemistry, Cancer, Cell cycle, Cell Cycle Checkpoints - drug effects, Cell Line, Tumor, Chemosensitization, Chromatin, Colon, Colon cancer, Colonic Neoplasms - drug therapy, Colorectal cancer, Colorectal carcinoma, Cytotoxicity, C‐terminal binding protein (CtBP) interacting protein, Damage, Deoxyribonucleic acid, DNA, DNA damage, DNA Damage - drug effects, DNA repair, DNA Repair - drug effects, Event-related potentials, Female, Gene Expression Regulation, HCT116 Cells, HEK293 Cells, Histone acetyltransferase, Histone Acetyltransferases - genetics, Histone Acetyltransferases - metabolism, Histone deacetylase, Histone Deacetylases - genetics, Histone Deacetylases - metabolism, Homologous recombination, Homology, Humans, Isothiocyanates - pharmacology, Lysine, Male, Mustard Plant - chemistry, Non-homologous end joining, Oral administration, Outerwear, p300-CBP Transcription Factors - genetics, p300-CBP Transcription Factors - metabolism, Polyposis, Polyps, Proteins, Rats, Rats, Inbred F344, Repair, Sulforaphane, sulforaphane analogs, Tetrazoles, Tetrazoles - pharmacology, Therapeutic applications, Toxicity, Vegetables - chemistry, Wasabia - chemistry