Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation

Abstract

Despite aggressive therapies, the prognosis of children with high-risk medulloblastoma is still poor, thus underscoring the need to develop novel treatment strategies. Here, we report that histone deacetylase inhibitors (HDACI), that is, MS-275, valproic acid or SAHA, provide a novel strategy for sensitization of medulloblastoma to DNA-damaging drugs such as Doxorubicin, VP16 and Cisplatin by promoting p53-dependent, mitochondrial apoptosis. Mechanistic studies reveal that single-agent treatment with MS-275 causes acetylation of the non-histone protein Ku70, an event reported to release Bax from Ku70, whereas DNAdamaging drugs trigger p53 acetylation and accumulation. Combined treatment with MS-275 and Doxorubicin or VP16 cooperates to promote binding of p53 to Bax and p53-dependent Bax activation, resulting in enhanced loss of mitochondrial membrane potential, cytochrome c release and caspase-dependent apoptosis. Overexpression of Bcl-2 almost completely abolishes the MS-275-mediated chemosensitization, underlining the importance of the mitochondrial pathway for inducing apoptosis. Also, MS-275 cooperates with chemotherapeutics to inhibit long-term clonogenic survival. Most importantly, MS-275 increases chemotherapeutic drug-induced apoptosis in primary medulloblastoma samples, and cooperates with Doxorubicin to suppress medulloblastoma growth in an in vivo model, which underscores the clinical relevance of the findings. Thus, HDACI such as MS-275 present a promising approach for chemosensitization of medulloblastoma by enhancing mitochondrial apoptosis in a p53-dependent manner. These findings have important clinical implications for the design of experimental treatment protocols for medulloblastoma.

Identification of a novel synergistic induction of cell death by Smac mimetic and HDAC inhibitors in acute myeloid leukemia cells

“…Beyond AML, we previously demonstrated in several cancer entities that Smac mimetics are potent sensitizers to programmed cell death and prime for death receptor-, chemotherapy-or radiation-induced apoptosis [21,22,[33][34][35][36][37][38][39][40][41]. Also, we reported in the past that HDACIs can sensitize cancer cells to cell death induced by death receptor ligands or anticancer drugs [42][43][44].…”

Histone and Non-Histone Targets of Dietary Deacetylase Inhibitors

“…Tributyrin shares p21WAF1 as a common gene target for de-repression in cancer cells 41 . Similar to butyrate, tributyrin has also been shown to acetylate p53 42 , and valproic acid has been shown to acetylate Ku70 in medulloblastoma cells 43 . More recently, it was reported that the ketone body d-β-hydroxybutyrate (βOHB) (IC 50 : 2~5mM) is an endogenous and specific inhibitor of class I HDACs.…”

Mitochondria: gatekeepers of response to chemotherapy

“…This has been convincingly demonstrated with many “priming” agents[27,54,58–60]. These priming agents, with diverse targets including histone deacetylases and PI3K, modify levels of the BCL-2 family to improve responses to cytotoxic chemotherapy[54,59]. In addition, a novel class of agents, BH3 mimetics, have been shown to potently and specifically inhibit several anti-apoptotic members of the BCL-2 family including BCL-2, BCL-X L and BCL-W.…”