Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium

Blaheta, Roman A.; Michaelis, Martin; Natsheh, Iyad; Hasenberg, Christoph; Weich, Eva; Relja, Borna; Jonas, Dietger; Činátl, Jindřich

doi:10.1038/sj.bjc.6603777

Cited by 33 publications

(32 citation statements)

References 37 publications

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“…Other authors showed similar results in anaplastic thyroid cancer cells [22]. It was suggested that the antitumour activity of doxorubicin, relying on its binding to DNA and the inhibition of topoisomerase II, is enhanced through histone acetylation and increased apoptosis as shown by the increased caspase 3 activation and the enhancement of doxorubicininduced G2 cell cycle arrest [32]. We observed an interesting response rate with the combination of valproic acid and doxorubicin that has not been previously reported with doxorubicin alone in two previous small studies; one patient among 11 and none among six showed partial response with second-line doxorubicin alone [5,6].…”

Section: Toxic Death 2 (4) 2 (4)supporting

confidence: 64%

Valproate–doxorubicin: promising therapy for progressing mesothelioma. A phase II study

Scherpereel

Berghmans²,

Lafitte³

et al. 2010

Eur Respir J

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No treatment is recommended for patients with malignant mesothelioma (MM) failing after first-line cisplatin-based chemotherapy. In vitro data suggested that valproic acid, a histone deacetylase inhibitor (HDACi), had a proapoptotic effect and synergised with doxorubicin to induce apoptosis in MM cells. Our primary end-point was to determine response rate of combined valproic acid and doxorubicin in patients with unresectable MM failing after platinum-based chemotherapy.Treatment consisted of doxorubicin (60 mg?m -2 ) plus valproic acid. An interim analysis for response rate was planned after the first 16 registered patients. All the cases were centrally reviewed.From July 2006 to March 2009, 45 eligible patients with pleural MM were registered. The majority of the patients were male (73%), had a performance status (PS) o80 (76%) and an epithelioid subtype (80%). There were seven partial responses (response rate 16%; 95% CI 3-25%), all in patients with PS 80-100. The best disease control rate was 36% (95% CI 22-51%). Two toxic deaths were observed (febrile neutropenia and cerebral thrombotic event), both in patients with poor PS (60-70).Valproic acid, an HDACi, plus doxorubicin appeared an effective chemotherapy regimen in good PS (80-100) patients with refractory or recurrent MM, for which no standard therapy was available.

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Section: Toxic Death 2 (4) 2 (4)supporting

confidence: 64%

Valproate–doxorubicin: promising therapy for progressing mesothelioma. A phase II study

Scherpereel

Berghmans²,

Lafitte³

et al. 2010

Eur Respir J

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“…Also in p53 independent models, the two drugs may have similar effects, as both compounds have been shown to enhance the levels of p73 and p21. 12,30,31 In our study, the combination had no effect in cell lines with deleted or mutated p53, whereas there was an effect in patient samples with mutated p53, although these were mainly among the less sensitive samples (Figures 2 and 3). Further examination of mechanisms underlying the synergistic interaction of the combination in both p53 dependent and independent models is warranted.…”

Section: Discussionmentioning

confidence: 68%

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

et al. 2011

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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.

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“…Coincidentally, valproate is a potent inhibitor of class I and class II HDAC. In vitro studies have shown antineoplastic effects of valproate in tumor cell lines of a wide range of human cancers, including prostate cancer (2), breast cancer (3,4), endometrial cancer (4,5), teratocarcinoma (6), hematologic cancer (7), cervical cancer (8), neuroblastoma (9), and thoracic (lung, esophagus, and pleura) cancers (5). Of particular interest, and with potentially important clinical relevance, is the finding of strong antineoplastic activity of valproate in chemotherapy-resistant cancer cells (9).…”

Section: Introductionmentioning

confidence: 99%

Cancer Risk in Long-term Users of Valproate: A Population-Based Case-Control Study

Hallas

Friis²,

Bjerrum³

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Inhibitors of histone deacetylases (HDAC) have shown promise as targeted cancer therapy. Valproate, an older anticonvulsant, has been shown to possess HDAC inhibitory activity. We undertook this casecontrol study to clarify whether long-term users of valproate had a reduced cancer incidence. If so, it would support HDAC inhibition as a pharmacologic principle in chemoprevention. Methods: We identified 149,417 incident cancer cases in Denmark during the study period 2000 through 2005, and 597,668 age-and gender-matched controls. Data on history of cancer, past hospital admission diagnoses, and prescription history were obtained from the Danish Cancer Registry, the Danish National Patient Registry, and the Danish Prescription Registry. Primary exposure to valproate was defined as a cumulative dose of minimum 1,500 g within the past 5 years.

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Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium

Cited by 33 publications

References 37 publications

Valproate–doxorubicin: promising therapy for progressing mesothelioma. A phase II study

Valproate–doxorubicin: promising therapy for progressing mesothelioma. A phase II study

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

Cancer Risk in Long-term Users of Valproate: A Population-Based Case-Control Study

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