Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia

Abstract

Although TP53 mutations are rare in acute myeloid leukemia (AML), wild type p53 function is habitually annulled through overexpression of MDM2 or through various mechanisms including epigenetic silencing by histone deacetylases (HDACs). We hypothesized that co-inhibition of MDM2 and HDACs, with nutlin-3 and valproic acid (VPA) would additively inhibit growth in leukemic cells expressing wild type TP53 and induce p53-mediated apoptosis. In vitro studies with the combination demonstrated synergistic induction of apoptosis in AML cell lines and patient cells. Nutlin-3 and VPA co-treatment resulted in massive induction of p53, acetylated p53 and p53 target genes in comparison with either agent alone, followed by p53 dependent cell death with autophagic features. In primary AML cells, inhibition of proliferation by the combination therapy correlated with the CD34 expression level of AML blasts. To evaluate the combination in vivo, we developed an orthotopic, NOD/SCID IL2rg null xenograft model of MOLM-13 (AML FAB M5a; wild type TP53) expressing firefly luciferase. Survival analysis and bioluminescent imaging demonstrated the superior in vivo efficacy of the dual inhibition of MDM2 and HDAC in comparison with controls. Our results suggest the concomitant targeting of MDM2-p53 and HDAC inhibition, may be an effective therapeutic strategy for the treatment of AML.

Nanoparticles Engineered with Rituximab and Loaded with Nutlin-3 Show Promising Therapeutic Activity in B-Leukemic Xenografts

“…So far, administration of Nutlin-3 in mouse models of disease has been conducted mostly per os, with a huge amount of drugs required (200-400 mg/kg twice a day) and some difficulties in giving the correct amount to each mouse (1,(4)(5)(6)(7). To improve the delivery and efficacy of this drug for the treatment of solid tumors, recent studies have used Nutlin-3 encapsulated into poly (lactide-co-glycolide) (PLGA) nanoparticles (NP; refs.…”

Chloroquine and Valproic Acid Combined Treatment in Vitro has Enhanced Cytotoxicity in an Osteosarcoma Cell Line

“…Chuan-Kun Wang*, Xi-Dong Yu, Qiang Li, Gang Xie, Yue Teng broad spectrum of cancer cells (Shan et al, 2012;Sidana et al, 2012;Jasek et al, 2012;Kwiecińska et al, 2012;Mackenzie et al, 2013) through the increase histone acetylation and apoptosis related gene expression activation, but the detailed mechanisms are still not clearly (Kwiecińska et al, 2011;Xie et al, 2012;McCormack et al, 2013;Nie et al, 2013).…”

Nitroreductase, a Near-Infrared Reporter Platform for In Vivo Time-Domain Optical Imaging of Metastatic Cancer

“…GFP and bioluminescence images were acquired as previously described (3,25). Time-domain imaging of NTR/ CytoCy5S fluorescence was acquired 30 to 60 minutes following administration of 69 mg CytoCy5S in a 5% Cremaphore EL solution in saline (100 mL) intravenously via the dorsal tail vein.…”

“…A 38-mm diameter linear volume resonator was used for transmission and reception of radiofrequency (RF) radiation. After a TriPilot scan, a T 1 -weighted FLASH pulse sequence (echo time (TE)/repetition time (TR) ¼ 3.416 ms/247 ms, 25 flip angle, 0.7 mm slice thickness, 8 consecutive slices, 3.0 Â 3.0 cm 2 field-ofview, 117 Â 117 mm 2 in-plane resolution) was used to scan axially through the lungs to localize the lung tumor. The acquisition was respiratory triggered to minimize motion artifacts.…”