Effects of histone deacetylase inhibitory prodrugs on epigenetic changes and DNA damage response in tumor and heart of glioblastoma xenograft.
The histone deacetylase (HDAC) inhibitory prodrugs of butyric (AN7) and valproic (AN446) acids, which release the active acids upon metabolic degradation, were studied examining their differential effects on the viability, HDAC inhibitory activity and the DNA damage response (DDR), in glioblastoma cell and normal human astrocytes (NHAs). In xenografts of glioblastoma, AN7 or AN446 given or the combination of each of them with Dox augmented the anticancer activity of Dox and protected the heart from its toxicity. In order to determine the processes underlying these opposing effects, the changes induced by these treatments on the epigenetic landscape, the DDR, and fibrosis were compared in tumors and hearts of glioblastoma xenografts. The potency of AN7 and AN446 as HDAC inhibitors was correlated with their effects on the viability of the cancer and non-cancer cells. The prodrugs affected the epigenetic landscape and the DDR in a tissue-specific and context-dependent manner. Findings suggest that the selectivity of the prodrugs could be attributed to their different effects on histone modification patterns in normal vs. transformed tissues. Further studies are warranted to substantiate the potential of AN446 as a new anticancer drug for glioblastoma patients.
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Rabin Medical Center-Beilinson Campus, 49100, Petah Tikva, Israel.
Nataly
N
Tarasenko
Department of Chemistry, Bar-Ilan University, 52900, Ramat-Gan, Israel.
Abraham
A
Nudelman
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Rabin Medical Center-Beilinson Campus, 49100, Petah Tikva, Israel.|Division of Hematology, Sheba Medical Center, Tel Hashomer, 52620, Ramat Gan, Israel.
Gabriela
G
Rozic
Department of Biochemistry and Genetics, La Trobe University, La Trobe Institute for Molecular Science, Bundoora, VIC, Australia.
Suzanne M
SM
Cutts
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Rabin Medical Center-Beilinson Campus, 49100, Petah Tikva, Israel. adarep@post.tau.ac.il.
Ada
A
Rephaeli
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation / Q000187:drug effects; D008819:Mice, Nude; D009206:Myocardium / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011355:Prodrugs; D004317:Doxorubicin; D006655:Histone Deacetylases
DNA damage response; Doxorubicin; Glioblastoma; H3 lysine 27 methylation; H3 lysine 56 acetylation; Histone deacetylase inhibitors