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Novel combination of histone methylation modulators with therapeutic synergy against acute myeloid leukemia in vitro and in vivo

Acute myeloid leukemia (AML) is a hematological malignancy with rapid disease progression and often becomes lethal without treatment. Development of effective new therapies is essential to improve the clinical outcome of AML patients. Enhancer of zeste homolog 2 (EZH2) and lysine specific demethylas... Full description

Journal Title: Cancer letters 2018-01-28, Vol.413, p.35-45
Main Author: Wen, Shijun
Other Authors: Wang, Jiankang , Liu, Panpan , Li, Yiqing , Lu, Wenhua , Hu, Yumin , Liu, Jinyun , He, Zhiyuan , Huang, Peng
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: Ireland: Elsevier B.V
ID: ISSN: 0304-3835
Link: https://www.ncbi.nlm.nih.gov/pubmed/29069576
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title: Novel combination of histone methylation modulators with therapeutic synergy against acute myeloid leukemia in vitro and in vivo
format: Article
creator:
  • Wen, Shijun
  • Wang, Jiankang
  • Liu, Panpan
  • Li, Yiqing
  • Lu, Wenhua
  • Hu, Yumin
  • Liu, Jinyun
  • He, Zhiyuan
  • Huang, Peng
subjects:
  • Acute myeloid leukemia
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols - pharmacology
  • Apoptosis
  • Apoptosis - drug effects
  • Bcl-2 protein
  • Benzamides - pharmacology
  • Cancer
  • Cancer therapies
  • Chromatin
  • Clinical trials
  • Cytochrome
  • Cytotoxicity
  • DNA methylation
  • Dose-Response Relationship, Drug
  • Drug combination
  • Drug resistance
  • Drug Synergism
  • Drug therapy
  • Drug therapy, Combination
  • Electron transport
  • Energy Metabolism - drug effects
  • Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors
  • Enhancer of Zeste Homolog 2 Protein - genetics
  • Enhancer of Zeste Homolog 2 Protein - metabolism
  • Enzyme Inhibitors - pharmacology
  • Enzymes
  • Epigenesis, Genetic - drug effects
  • Epigenetic inheritance
  • Epigenetics
  • EZH2
  • FDA approval
  • Female
  • Glycolysis
  • Health aspects
  • Hematology
  • Histone Demethylases - antagonists & inhibitors
  • Histone Demethylases - genetics
  • Histone Demethylases - metabolism
  • Histones - metabolism
  • HL-60 Cells
  • Homology
  • Humans
  • Hydrazines - pharmacology
  • Immunoglobulins
  • Leukemia
  • Leukemia, Myeloid, Acute - drug therapy
  • Leukemia, Myeloid, Acute - enzymology
  • Leukemia, Myeloid, Acute - genetics
  • Leukemia, Myeloid, Acute - pathology
  • LSD1
  • Lysine
  • Malignancy
  • Medical treatment
  • Metabolism
  • Methylation
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondria
  • Mitochondria - drug effects
  • Mitochondria - metabolism
  • Myeloid leukemia
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2 - metabolism
  • Pyridones - pharmacology
  • RNA polymerase
  • Sulfonamides - pharmacology
  • Synergistic effect
  • Time Factors
  • Tumor Cells, Cultured
  • Up-Regulation
  • Xenograft Model Antitumor Assays
ispartof: Cancer letters, 2018-01-28, Vol.413, p.35-45
description: Acute myeloid leukemia (AML) is a hematological malignancy with rapid disease progression and often becomes lethal without treatment. Development of effective new therapies is essential to improve the clinical outcome of AML patients. Enhancer of zeste homolog 2 (EZH2) and lysine specific demethylase 1 (LSD1) play important roles in epigenetic regulation and their altered expressions have been observed in cancer. Although EZH2 and LSD1 have opposite histone methylation functions, we found that both enzymes were paradoxically up-regulated in AML cells. Importantly, a combined inhibition of EZH2 and LSD1 resulted in a synergistic activity against AML in vitro and in vivo. Such synergy was mechanistically correlated with up-regulation of H3K4me1/2 and H3K9Ac and down-regulation of H3K27me3, leading to a decrease of anti-apoptotic protein Bcl-2. These epigenetic alterations also compromised the mitochondrial respiration capacity and glycolytic activity and resulted in ATP depletion, a key event contributing to the potent cytotoxic effect of the drug combination. Taken together, our work identified a novel therapeutic approach against AML by combining two small molecules that inhibit different histone methylation-modulating proteins with apparently opposite enzyme activities. Such a new drug combination strategy likely has significant clinical implications since epigenetic modulators are currently in clinical trials. •Functionally opposite EZH2 and LSD1 were found to be up-regulated in the same AML cell lines and AML patient samples.•Co-inhibition of LSD1 and EZH2 substantially resulted in H3K9Ac accumulation, Bcl-2 depletion, and insufficient energy supply.•Combination of LSD1 inhibitor SP2509 and EZH2 inhibitor EPZ6438 has achieved a strong synergistic anti-AML effect.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0304-3835
fulltext: fulltext
issn:
  • 0304-3835
  • 1872-7980
url: Link


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titleNovel combination of histone methylation modulators with therapeutic synergy against acute myeloid leukemia in vitro and in vivo
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creatorWen, Shijun ; Wang, Jiankang ; Liu, Panpan ; Li, Yiqing ; Lu, Wenhua ; Hu, Yumin ; Liu, Jinyun ; He, Zhiyuan ; Huang, Peng
creatorcontribWen, Shijun ; Wang, Jiankang ; Liu, Panpan ; Li, Yiqing ; Lu, Wenhua ; Hu, Yumin ; Liu, Jinyun ; He, Zhiyuan ; Huang, Peng
descriptionAcute myeloid leukemia (AML) is a hematological malignancy with rapid disease progression and often becomes lethal without treatment. Development of effective new therapies is essential to improve the clinical outcome of AML patients. Enhancer of zeste homolog 2 (EZH2) and lysine specific demethylase 1 (LSD1) play important roles in epigenetic regulation and their altered expressions have been observed in cancer. Although EZH2 and LSD1 have opposite histone methylation functions, we found that both enzymes were paradoxically up-regulated in AML cells. Importantly, a combined inhibition of EZH2 and LSD1 resulted in a synergistic activity against AML in vitro and in vivo. Such synergy was mechanistically correlated with up-regulation of H3K4me1/2 and H3K9Ac and down-regulation of H3K27me3, leading to a decrease of anti-apoptotic protein Bcl-2. These epigenetic alterations also compromised the mitochondrial respiration capacity and glycolytic activity and resulted in ATP depletion, a key event contributing to the potent cytotoxic effect of the drug combination. Taken together, our work identified a novel therapeutic approach against AML by combining two small molecules that inhibit different histone methylation-modulating proteins with apparently opposite enzyme activities. Such a new drug combination strategy likely has significant clinical implications since epigenetic modulators are currently in clinical trials. •Functionally opposite EZH2 and LSD1 were found to be up-regulated in the same AML cell lines and AML patient samples.•Co-inhibition of LSD1 and EZH2 substantially resulted in H3K9Ac accumulation, Bcl-2 depletion, and insufficient energy supply.•Combination of LSD1 inhibitor SP2509 and EZH2 inhibitor EPZ6438 has achieved a strong synergistic anti-AML effect.
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0ISSN: 0304-3835
1EISSN: 1872-7980
2DOI: 10.1016/j.canlet.2017.10.015
3PMID: 29069576
languageeng
publisherIreland: Elsevier B.V
subjectAcute myeloid leukemia ; Animals ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Bcl-2 protein ; Benzamides - pharmacology ; Cancer ; Cancer therapies ; Chromatin ; Clinical trials ; Cytochrome ; Cytotoxicity ; DNA methylation ; Dose-Response Relationship, Drug ; Drug combination ; Drug resistance ; Drug Synergism ; Drug therapy ; Drug therapy, Combination ; Electron transport ; Energy Metabolism - drug effects ; Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors ; Enhancer of Zeste Homolog 2 Protein - genetics ; Enhancer of Zeste Homolog 2 Protein - metabolism ; Enzyme Inhibitors - pharmacology ; Enzymes ; Epigenesis, Genetic - drug effects ; Epigenetic inheritance ; Epigenetics ; EZH2 ; FDA approval ; Female ; Glycolysis ; Health aspects ; Hematology ; Histone Demethylases - antagonists & inhibitors ; Histone Demethylases - genetics ; Histone Demethylases - metabolism ; Histones - metabolism ; HL-60 Cells ; Homology ; Humans ; Hydrazines - pharmacology ; Immunoglobulins ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - enzymology ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - pathology ; LSD1 ; Lysine ; Malignancy ; Medical treatment ; Metabolism ; Methylation ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - metabolism ; Myeloid leukemia ; Proteins ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Pyridones - pharmacology ; RNA polymerase ; Sulfonamides - pharmacology ; Synergistic effect ; Time Factors ; Tumor Cells, Cultured ; Up-Regulation ; Xenograft Model Antitumor Assays
ispartofCancer letters, 2018-01-28, Vol.413, p.35-45
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0Wen, Shijun
1Wang, Jiankang
2Liu, Panpan
3Li, Yiqing
4Lu, Wenhua
5Hu, Yumin
6Liu, Jinyun
7He, Zhiyuan
8Huang, Peng
title
0Novel combination of histone methylation modulators with therapeutic synergy against acute myeloid leukemia in vitro and in vivo
1Cancer letters
addtitleCancer Lett
descriptionAcute myeloid leukemia (AML) is a hematological malignancy with rapid disease progression and often becomes lethal without treatment. Development of effective new therapies is essential to improve the clinical outcome of AML patients. Enhancer of zeste homolog 2 (EZH2) and lysine specific demethylase 1 (LSD1) play important roles in epigenetic regulation and their altered expressions have been observed in cancer. Although EZH2 and LSD1 have opposite histone methylation functions, we found that both enzymes were paradoxically up-regulated in AML cells. Importantly, a combined inhibition of EZH2 and LSD1 resulted in a synergistic activity against AML in vitro and in vivo. Such synergy was mechanistically correlated with up-regulation of H3K4me1/2 and H3K9Ac and down-regulation of H3K27me3, leading to a decrease of anti-apoptotic protein Bcl-2. These epigenetic alterations also compromised the mitochondrial respiration capacity and glycolytic activity and resulted in ATP depletion, a key event contributing to the potent cytotoxic effect of the drug combination. Taken together, our work identified a novel therapeutic approach against AML by combining two small molecules that inhibit different histone methylation-modulating proteins with apparently opposite enzyme activities. Such a new drug combination strategy likely has significant clinical implications since epigenetic modulators are currently in clinical trials. •Functionally opposite EZH2 and LSD1 were found to be up-regulated in the same AML cell lines and AML patient samples.•Co-inhibition of LSD1 and EZH2 substantially resulted in H3K9Ac accumulation, Bcl-2 depletion, and insufficient energy supply.•Combination of LSD1 inhibitor SP2509 and EZH2 inhibitor EPZ6438 has achieved a strong synergistic anti-AML effect.
subject
0Acute myeloid leukemia
1Animals
2Antineoplastic Combined Chemotherapy Protocols - pharmacology
3Apoptosis
4Apoptosis - drug effects
5Bcl-2 protein
6Benzamides - pharmacology
7Cancer
8Cancer therapies
9Chromatin
10Clinical trials
11Cytochrome
12Cytotoxicity
13DNA methylation
14Dose-Response Relationship, Drug
15Drug combination
16Drug resistance
17Drug Synergism
18Drug therapy
19Drug therapy, Combination
20Electron transport
21Energy Metabolism - drug effects
22Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors
23Enhancer of Zeste Homolog 2 Protein - genetics
24Enhancer of Zeste Homolog 2 Protein - metabolism
25Enzyme Inhibitors - pharmacology
26Enzymes
27Epigenesis, Genetic - drug effects
28Epigenetic inheritance
29Epigenetics
30EZH2
31FDA approval
32Female
33Glycolysis
34Health aspects
35Hematology
36Histone Demethylases - antagonists & inhibitors
37Histone Demethylases - genetics
38Histone Demethylases - metabolism
39Histones - metabolism
40HL-60 Cells
41Homology
42Humans
43Hydrazines - pharmacology
44Immunoglobulins
45Leukemia
46Leukemia, Myeloid, Acute - drug therapy
47Leukemia, Myeloid, Acute - enzymology
48Leukemia, Myeloid, Acute - genetics
49Leukemia, Myeloid, Acute - pathology
50LSD1
51Lysine
52Malignancy
53Medical treatment
54Metabolism
55Methylation
56Mice, Inbred BALB C
57Mice, Nude
58Mitochondria
59Mitochondria - drug effects
60Mitochondria - metabolism
61Myeloid leukemia
62Proteins
63Proto-Oncogene Proteins c-bcl-2 - metabolism
64Pyridones - pharmacology
65RNA polymerase
66Sulfonamides - pharmacology
67Synergistic effect
68Time Factors
69Tumor Cells, Cultured
70Up-Regulation
71Xenograft Model Antitumor Assays
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7He, Zhiyuan
8Huang, Peng
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titleNovel combination of histone methylation modulators with therapeutic synergy against acute myeloid leukemia in vitro and in vivo
authorWen, Shijun ; Wang, Jiankang ; Liu, Panpan ; Li, Yiqing ; Lu, Wenhua ; Hu, Yumin ; Liu, Jinyun ; He, Zhiyuan ; Huang, Peng
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0Acute myeloid leukemia
1Animals
2Antineoplastic Combined Chemotherapy Protocols - pharmacology
3Apoptosis
4Apoptosis - drug effects
5Bcl-2 protein
6Benzamides - pharmacology
7Cancer
8Cancer therapies
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10Clinical trials
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13DNA methylation
14Dose-Response Relationship, Drug
15Drug combination
16Drug resistance
17Drug Synergism
18Drug therapy
19Drug therapy, Combination
20Electron transport
21Energy Metabolism - drug effects
22Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors
23Enhancer of Zeste Homolog 2 Protein - genetics
24Enhancer of Zeste Homolog 2 Protein - metabolism
25Enzyme Inhibitors - pharmacology
26Enzymes
27Epigenesis, Genetic - drug effects
28Epigenetic inheritance
29Epigenetics
30EZH2
31FDA approval
32Female
33Glycolysis
34Health aspects
35Hematology
36Histone Demethylases - antagonists & inhibitors
37Histone Demethylases - genetics
38Histone Demethylases - metabolism
39Histones - metabolism
40HL-60 Cells
41Homology
42Humans
43Hydrazines - pharmacology
44Immunoglobulins
45Leukemia
46Leukemia, Myeloid, Acute - drug therapy
47Leukemia, Myeloid, Acute - enzymology
48Leukemia, Myeloid, Acute - genetics
49Leukemia, Myeloid, Acute - pathology
50LSD1
51Lysine
52Malignancy
53Medical treatment
54Metabolism
55Methylation
56Mice, Inbred BALB C
57Mice, Nude
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59Mitochondria - drug effects
60Mitochondria - metabolism
61Myeloid leukemia
62Proteins
63Proto-Oncogene Proteins c-bcl-2 - metabolism
64Pyridones - pharmacology
65RNA polymerase
66Sulfonamides - pharmacology
67Synergistic effect
68Time Factors
69Tumor Cells, Cultured
70Up-Regulation
71Xenograft Model Antitumor Assays
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8Huang, Peng
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abstractAcute myeloid leukemia (AML) is a hematological malignancy with rapid disease progression and often becomes lethal without treatment. Development of effective new therapies is essential to improve the clinical outcome of AML patients. Enhancer of zeste homolog 2 (EZH2) and lysine specific demethylase 1 (LSD1) play important roles in epigenetic regulation and their altered expressions have been observed in cancer. Although EZH2 and LSD1 have opposite histone methylation functions, we found that both enzymes were paradoxically up-regulated in AML cells. Importantly, a combined inhibition of EZH2 and LSD1 resulted in a synergistic activity against AML in vitro and in vivo. Such synergy was mechanistically correlated with up-regulation of H3K4me1/2 and H3K9Ac and down-regulation of H3K27me3, leading to a decrease of anti-apoptotic protein Bcl-2. These epigenetic alterations also compromised the mitochondrial respiration capacity and glycolytic activity and resulted in ATP depletion, a key event contributing to the potent cytotoxic effect of the drug combination. Taken together, our work identified a novel therapeutic approach against AML by combining two small molecules that inhibit different histone methylation-modulating proteins with apparently opposite enzyme activities. Such a new drug combination strategy likely has significant clinical implications since epigenetic modulators are currently in clinical trials. •Functionally opposite EZH2 and LSD1 were found to be up-regulated in the same AML cell lines and AML patient samples.•Co-inhibition of LSD1 and EZH2 substantially resulted in H3K9Ac accumulation, Bcl-2 depletion, and insufficient energy supply.•Combination of LSD1 inhibitor SP2509 and EZH2 inhibitor EPZ6438 has achieved a strong synergistic anti-AML effect.
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pubElsevier B.V
pmid29069576
doi10.1016/j.canlet.2017.10.015
orcididhttps://orcid.org/0000-0002-9347-8243