Resveratrol Sensitizes Acute Myelogenous Leukemia Cells to Histone Deacetylase Inhibitors through Reactive Oxygen Species-Mediated Activation of the Extrinsic Apoptotic Pathway

Abstract

Histone deacetylase inhibitors (HDACIs) activate the prosurvival nuclear factor-B (NF-B) pathway by hyperacetylating RelA/p65, whereas the chemopreventive agent resveratrol inhibits NF-B by activating the class III histone deacetylase Sirt1. Interactions between resveratrol and pan-HDACIs (vorinostat and panobinostat) were examined in human acute myelogenous leukemia (AML) cells. Pharmacologically achievable resveratrol concentrations (25-50 M) synergistically potentiated HDACI lethality in AML cell lines and primary AML blasts. Resveratrol antagonized RelA acetylation and NF-B activation in HDACI-treated cells. However, short hairpin RNA Sirt1 knockdown failed to modify HDACI sensitivity, which suggests that factors other than or in addition to Sirt1 activation contribute to resveratrol/HDACI interactions. These interactions were associated with death receptor 5 (DR5) up-regulation and caspase-8 activation, whereas cells expressing dominant-negative caspase-8 were substantially protected from resveratrol/ HDACI treatment, which suggests a significant functional role for the extrinsic apoptotic pathway in lethality. Exposure to resveratrol with HDACI induced sustained reactive oxygen species (ROS) generation, which was accompanied by increased levels of DNA double-strand breaks, as reflected in ␥H2A.X and comet assays. The free radical scavenger Mn(III)tetrakis(4-benzoic acid)porphyrin chloride blocked ROS generation, DR5 upregulation, caspase-8 activation, DNA damage, and apoptosis, which indicates a primary role for oxidative injury in lethality. Analyses of cell-cycle progression and 5-ethynyl-2Ј-deoxyuridine incorporation through flow cytometry revealed that resveratrol induced S-phase accumulation; this effect was abrogated by HDACI coadministration, which suggests that cells undergoing DNA synthesis may be particularly vulnerable to HDACI lethality. Collectively, these findings indicate that resveratrol interacts synergistically with HDACIs in AML cells through multiple ROS-dependent actions, including death receptor up-regulation, extrinsic apoptotic pathway activation, and DNA damage induction. They also raise the possibility that S-phase cells may be particularly susceptible to these actions.

The blueberry component pterostilbene has potent anti-myeloma activity in bortezomib-resistant cells

“…The latter can 'sensitize' resistant cells to chemotherapeutic agents by overcoming one or more mechanisms of chemoresistance (5). Various drug-resistant tumors, including lung carcinoma, pancreatic cancer, acute myeloid leukemia, promyelocytic leukemia, and MM, can be sensitized by resveratrol (6)(7)(8)(9). Pterostilbene (3,5-dimethoxy-40-hydroxystilbene; Pter) is found mainly in blueberries, grapes and tree wood (10).…”

Reverse chemomodulatory effects of the SIRT1 activators resveratrol and SRT1720 in Ewing’s sarcoma cells: resveratrol suppresses and SRT1720 enhances etoposide- and vincristine-induced anticancer activity

“…For instance, resveratrol has been shown to synergize with paclitaxel (Jazirehi and Bonavida 2004), etoposide (Amiri et al 2013), gemcitabine (Harikumar et al 2010), bortezomib and thalidomide (Bhardwaj et al 2007) and histone deacetylase inhibitors (HDACi) (Yaseen et al 2012). With respect to childhood cancers, it has been demonstrated to cooperate with etoposide, doxorubicin, cytarabine, actinomycin D, methotrexate and paclitaxel (Fulda and Debatin 2004), TRAIL (Fulda and Debatin 2005) and immunotherapy (Soto et al 2011) in neuroblastoma, with decitabine in medulloblastoma (Patties et al 2013) and with vincristine in retinoblastoma (Mahida et al 2013).…”

Cancer Preventive and Therapeutic Properties of Fruits and Vegetables Against Commonly Occurring Cancers in Humans

“…87 It also sensitizes AML cells to histone deacetylase inhibitors, through inhibiting the activity of NF-κB, thus activating the class III histone deacetylase Sirt. 88 In addition, it has also been proven to sensitize doxorubicin-resistant AML cells via downregulation of MRP1 expression. 79 Moreover, in K562/ IMA-3 cell lines resistant to imatinib, resveratrol induced apoptosis by activating caspase 3.…”