Overcoming resistance to histone deacetylase inhibitors in human leukemia with the redox modulating compound β-phenylethyl isothiocyanate

Hu, Yumin; Lu, Weiqin; Chen, Gang; Zhang, Hui; Jia, Yu; Wei, Yue; Yang, Hui; Zhang, Wan; Fiskus, Warren; Bhalla, Kapil N.; Keating, Michael J.; Huang, Peng; Garcia‐Manero, Guillermo

doi:10.1182/blood-2009-11-256354

Cited by 97 publications

(96 citation statements)

References 34 publications

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“…We evaluated four parameters: histone acetylation 4 ; beclin 12,16 ; levels of TIMP1, IL-6, and MMP9 as markers of chemotherapy resistance 17 ; and a reactive oxygen species pathway (NRF2, CYBB, FOXO3, SOD1, SOD2, and GST-Pi) involved in HDACI resistance. 18 We could detect significant levels of histone acetylation in 30% of patients. This low rate is probably related to the low sensitivity of the assay used (Western blot) as opposed to that of other assays such as enzyme-linked immunosorbent assay.…”

Section: Discussionmentioning

confidence: 84%

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Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Garcia‐Manero

Tambaro

Bekele

et al. 2012

JCO

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161

103

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A B S T R A C T PurposeTo evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Patients and MethodsPatients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m 2 intravenously (IV) daily ϫ 3 (days 4 to 6), and cytarabine 1.5 g/m 2 IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely. ResultsAfter a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival. ConclusionThe combination of vorinostat with idarubicin and cytarabine is safe and active in AML.

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Section: Discussionmentioning

confidence: 84%

“…Finally, we explored upregulation at the mRNA levels of a series of genes involved in chemotherapy resistance 17 and reactive oxygen species. 18 All of these genes were found to be upregulated during therapy. Of importance, levels of the transcription factor NRF2 and CYBB were associated with a trend toward improved survival.…”

Section: Discussionmentioning

confidence: 99%

Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Garcia‐Manero

Tambaro

Bekele

et al. 2012

JCO

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161

103

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“…In addition depletion of GSH, that is a ROS scavenger, increases the effects of vorinostat on AML cells 69 .…”

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confidence: 99%

Histone deacetylase inhibitors in cancer therapy. A review

Hraběta¹,

Stiborová²,

Adam³

et al. 2014

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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a Background. Despite recent success toward discovery of more effective anticancer drugs, chemoresistance remains a major cause of treatment failure. There is emerging evidence that epigenetics plays a key role in the development of the resistance. Epigenetic regulators such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) play an important role in gene expression. The latter are found to be commonly linked with many types of cancers and influence cancer development. Overall, histone acetylation is being investigated as a therapeutic target because of its importance in regulating gene expression. This review summarizes mechanisms of the anticancer effects of histone deacetylase (HDAC) inhibitors and the results of clinical studies. Results. Different HDAC inhibitors induce cancer cell death by different mechanisms that include changes in gene expression and alteration of both histone and non-histone proteins. Enhanced histone acetylation in tumors results in modification of expression of genes involved in cell signaling. Inhibition of HDACs causes changed expression in 2-10 % of genes involved in important biological processes. The results of experiments and clinical studies demonstrate that combination of HDAC inhibitors with some anticancer drugs have synergistic or additive effects. Conclusions. Even though many biological effects of HDAC inhibitors have been found, most of the mechanisms of their action remain unclear. In addition, their use in combination with other drugs and the combination regime need to be investigated. The discovery of predictive factors is also necessary. Finally, a key question is whether the pan-HDAC inhibitors or the selective inhibitors will be more efficient for different types of cancers.

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“…We reason that modulating gemcitabineinduced redox regulatory mechanisms by reducing GSH pool may affect cell survival and drug sensitivity. PEITC, a novel compound that has been reported to deplete GSH and subsequently elevate oxidative stress (15,17), may circumvent such protection and enhance the antipancreatic cancer activity of gemcitabine.…”

Section: Discussionmentioning

confidence: 99%

“…b-Phenylethyl isothiocyanate (PEITC), a natural compound found in cruciferous vegetables, depletes GSH and selectively kills cancer cells while sparing healthy cells (14)(15)(16)(17). Given the fact that stimulation of ROS is generated by gemcitabine in PDAC cells, we hypothesized that the cells increase cellular GSH to prevent oxidative damage and that PEITC enhances the effect of gemcitabine-induced ROS through the redox modulation.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

Gocho

Aguilar

et al. 2015

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) frequently develops therapeutic resistances, which can be divided into extrinsic and intrinsic resistance. The extrinsic resistance that arises from the surrounding dense tumor stroma is much better understood. However, the mechanisms of intrinsic resistance are not well understood. Here, we report that reactive oxygen species (ROS) induced by gemcitabine treatment, a newly discovered cytotoxic activity, served as a probe in our study to reveal the mechanisms of the intrinsic therapeutic resistance. Our results showed that gemcitabine-induced ROS is generated by NOX and through the increase of p22 -phox expression via NF-kB activation. As a feedback mechanism, nuclear translocation of Nrf2 stimulated the transcription of cytoprotective antioxidant genes, especially genes encoding enzymes that catalyze glutathione (GSH) production to reduce elevated ROS as an intrinsic resistance countermeasure. RNAi-mediated depletion of Nrf2 or addition of b-phenylethyl isothiocyanate inhibited the ROS detoxification process by reducing GSH levels, which, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our study suggests that a redoxmediated pathway contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC has a selective cytotoxic effect against pancreatic cancer cells in vivo and could thus prove valuable as a cancer treatment. Mol Cancer Ther; 14(3); 788-98.Ó2014 AACR.

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Overcoming resistance to histone deacetylase inhibitors in human leukemia with the redox modulating compound β-phenylethyl isothiocyanate

Cited by 97 publications

References 34 publications

Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Histone deacetylase inhibitors in cancer therapy. A review

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

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