Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51

Xie, Chengzhi; Drenberg, Christina D.; Edwards, Holly; Caldwell, J. Timothy; Chen, Wei; Inaba, Hiroto; Xu, Xuelian; Buck, Steven; Taub, Jeffrey W.; Baker, Sharyn D.; Ge, Yubin

doi:10.1371/journal.pone.0079106

Cited by 79 publications

(98 citation statements)

References 52 publications

(51 reference statements)

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“…5A and B). Consistent with our previous studies, 38 CHK1 levels were decreased following panobinostat treatment and were accompanied by decreased levels of p-CDC25C. Surprisingly, MK-1775 treatment alone also caused significant decrease of CHK1, though it had no effect on CDC25C phosphorylation ( Fig.…”

Section: Panobinostat Synergistically Enhances Mk-1775-induced Cell Dsupporting

confidence: 92%

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Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo

Zhang

Edwards

et al. 2015

Cancer Biology & Therapy

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MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775-and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.

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Section: Panobinostat Synergistically Enhances Mk-1775-induced Cell Dsupporting

confidence: 92%

“…38,53,56 The present findings provide support for the clinical development of panobinostat in combination with MK-1775 for the treatment of AML.…”

Section: Discussionsupporting

confidence: 68%

Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo

Zhang

Edwards

et al. 2015

Cancer Biology & Therapy

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“…37,38,47,48 Recent evidence has also highlighted the role of NF-kB, DNA damage, cell cycle checkpoint, and DNA repair in HDACI lethality. [49][50][51][52] It therefore seemed plausible that complementary HDACI and MLN4924 MOAs might result in enhanced antileukemia activity. Indeed, the present results indicate that these agents interact synergistically against AML cell lines, primary AML/MDS cells, and LIC-enriched primitive cells, including those carrying diverse genetic mutations.…”

Section: Discussionmentioning

confidence: 99%

The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR

Zhou

Chen

Zhang

et al. 2016

Blood

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• The NAE inhibitor pevonedistat induces Chk1/Wee1 activation and the intra-S checkpoint, limiting its anti-AML efficacy.• The HDAC inhibitor belinostat potentiates the in vitro and in vivo activity of pevonedistat in AML by disrupting the DDR.Two classes of novel agents, NEDD8-activating enzyme (NAE) and histone deacetylase (HDAC) inhibitors, have shown single-agent activity in acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS). Here we examined mechanisms underlying interactions between the NAE inhibitor pevonedistat (MLN4924) and the approved HDAC inhibitor belinostat in AML/MDS cells. MLN4924/belinostat coadministration synergistically induced AML cell apoptosis with or without p53 deficiency or FLT3-internal tandem duplication (ITD), whereas p53 short hairpin RNA (shRNA) knockdown or enforced FLT3-ITD expression significantly sensitized cells to the regimen. MLN4924 blocked belinostat-induced antiapoptotic gene expression through nuclear factor-kB inactivation. Each agent upregulated Bim, and Bim knockdown significantly attenuated apoptosis. Microarrays revealed distinct DNA damage response (DDR) genetic profiles between individual vs combined MLN4924/belinostat exposure. Whereas belinostat abrogated the MLN4924-activated intra-S checkpoint through Chk1 and Wee1 inhibition/downregulation, cotreatment downregulated multiple homologous recombination and nonhomologous end-joining repair proteins, triggering robust double-stranded breaks, chromatin pulverization, and apoptosis. Consistently, Chk1 or Wee1 shRNA knockdown significantly sensitized AML cells to MLN4924. MLN4924/belinostat displayed activity against primary AML or MDS cells, including those carrying next-generation sequencingdefined poor-prognostic cancer hotspot mutations, and CD34

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“…However, there are many clinical trials investigating the role of HDACIs in combination therapies (NCT01242774, NCT01742793, NCT02061449, and NCT02145715, clinicaltrials.gov). Previous work from this lab has demonstrated the ability of HDACIs to synergize with standard chemotherapeutic agents, at least in part by enhancing DNA damage [28–31]. Importantly, we recently demonstrated that treatment with the pan-HDACI panobinostat (LBH589) was able to down-regulate CHK1 [28,29].…”

Section: Introductionmentioning

confidence: 99%

Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer

et al. 2015

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Pancreatic cancer remains a clinical challenge, thus new therapies are urgently needed. The selective Wee1 inhibitor MK-1775 has demonstrated promising results when combined with DNA damaging agents, and more recently with CHK1 inhibitors in various malignancies. We have previously demonstrated that treatment with the pan-histone deacetylase inhibitor panobinostat (LBH589) can cause down-regulation of CHK1. Accordingly, we investigated using panobinostat to down-regulate CHK1 in combination with MK-1775 to enhance cell death in preclinical pancreatic cancer models. We demonstrate that MK-1775 treatment results in increased H2AX phosphorylation, indicating increased DNA double-strand breaks, and activation of CHK1, which are both dependent on CDK activity. Combination of MK-1775 and panobinostat resulted in synergistic antitumor activity in six pancreatic cancer cell lines. Finally, our in vivo study using a pancreatic xenograft model reveals promising cooperative antitumor activity between MK-1775 and panobinostat. Our study provides compelling evidence that the combination of MK-1775 and panobinostat has antitumor activity in preclinical models of pancreatic cancer and supports the clinical development of panobinostat in combination with MK-1775 for the treatment of this deadly disease.

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Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51

Cited by 79 publications

References 52 publications

Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo

Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo

The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR

Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer

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