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APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells
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| Zeitschriftentitel: | Molecular Cancer Therapeutics |
|---|---|
| Personen und Körperschaften: | , , , , , , , |
| In: | Molecular Cancer Therapeutics, 17, 2018, 6, S. 1177-1186 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
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| Schlagwörter: |
| author_facet |
Local, Andrea Zhang, Hongying Benbatoul, Khalid D. Folger, Peter Sheng, Xia Tsai, Cheng-Yu Howell, Stephen B. Rice, William G. Local, Andrea Zhang, Hongying Benbatoul, Khalid D. Folger, Peter Sheng, Xia Tsai, Cheng-Yu Howell, Stephen B. Rice, William G. |
|---|---|
| author |
Local, Andrea Zhang, Hongying Benbatoul, Khalid D. Folger, Peter Sheng, Xia Tsai, Cheng-Yu Howell, Stephen B. Rice, William G. |
| spellingShingle |
Local, Andrea Zhang, Hongying Benbatoul, Khalid D. Folger, Peter Sheng, Xia Tsai, Cheng-Yu Howell, Stephen B. Rice, William G. Molecular Cancer Therapeutics APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells Cancer Research Oncology |
| author_sort |
local, andrea |
| spelling |
Local, Andrea Zhang, Hongying Benbatoul, Khalid D. Folger, Peter Sheng, Xia Tsai, Cheng-Yu Howell, Stephen B. Rice, William G. 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-17-1209 <jats:title>Abstract</jats:title> <jats:p>APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G0–G1 cell-cycle arrest, and triggers apoptosis in acute myeloid leukemia (AML) cells without producing myelosuppression in various animal species and humans. Differential gene expression analysis identified a pharmacodynamic effect on MYC expression, as well as induction of DNA repair and stress response pathways. APTO-253 was found to elicit a concentration- and time-dependent reduction in MYC mRNA expression and protein levels. Gene ontogeny and structural informatic analyses suggested a mechanism involving G-quadruplex (G4) stabilization. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)3]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253)3 stabilize G4 structures from telomeres, MYC, and KIT promoters but do not bind to non-G4 double-stranded DNA. Although APTO-253 exerts a host of mechanistic sequelae, the effect of APTO-253 on MYC expression and its downstream target genes, on cell-cycle arrest, DNA damage, and stress responses can be explained by the action of Fe(253)3 and APTO-253 on G-quadruplex DNA motifs. Mol Cancer Ther; 17(6); 1177–86. ©2018 AACR.</jats:p> APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells Molecular Cancer Therapeutics |
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American Association for Cancer Research (AACR), 2018 |
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| title |
APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_unstemmed |
APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_full |
APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_fullStr |
APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_full_unstemmed |
APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_short |
APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_sort |
apto-253 stabilizes g-quadruplex dna, inhibits myc expression, and induces dna damage in acute myeloid leukemia cells |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1535-7163.mct-17-1209 |
| publishDate |
2018 |
| physical |
1177-1186 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G0–G1 cell-cycle arrest, and triggers apoptosis in acute myeloid leukemia (AML) cells without producing myelosuppression in various animal species and humans. Differential gene expression analysis identified a pharmacodynamic effect on MYC expression, as well as induction of DNA repair and stress response pathways. APTO-253 was found to elicit a concentration- and time-dependent reduction in MYC mRNA expression and protein levels. Gene ontogeny and structural informatic analyses suggested a mechanism involving G-quadruplex (G4) stabilization. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)3]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253)3 stabilize G4 structures from telomeres, MYC, and KIT promoters but do not bind to non-G4 double-stranded DNA. Although APTO-253 exerts a host of mechanistic sequelae, the effect of APTO-253 on MYC expression and its downstream target genes, on cell-cycle arrest, DNA damage, and stress responses can be explained by the action of Fe(253)3 and APTO-253 on G-quadruplex DNA motifs. Mol Cancer Ther; 17(6); 1177–86. ©2018 AACR.</jats:p> |
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| author | Local, Andrea, Zhang, Hongying, Benbatoul, Khalid D., Folger, Peter, Sheng, Xia, Tsai, Cheng-Yu, Howell, Stephen B., Rice, William G. |
| author_facet | Local, Andrea, Zhang, Hongying, Benbatoul, Khalid D., Folger, Peter, Sheng, Xia, Tsai, Cheng-Yu, Howell, Stephen B., Rice, William G., Local, Andrea, Zhang, Hongying, Benbatoul, Khalid D., Folger, Peter, Sheng, Xia, Tsai, Cheng-Yu, Howell, Stephen B., Rice, William G. |
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| description | <jats:title>Abstract</jats:title> <jats:p>APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G0–G1 cell-cycle arrest, and triggers apoptosis in acute myeloid leukemia (AML) cells without producing myelosuppression in various animal species and humans. Differential gene expression analysis identified a pharmacodynamic effect on MYC expression, as well as induction of DNA repair and stress response pathways. APTO-253 was found to elicit a concentration- and time-dependent reduction in MYC mRNA expression and protein levels. Gene ontogeny and structural informatic analyses suggested a mechanism involving G-quadruplex (G4) stabilization. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)3]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253)3 stabilize G4 structures from telomeres, MYC, and KIT promoters but do not bind to non-G4 double-stranded DNA. Although APTO-253 exerts a host of mechanistic sequelae, the effect of APTO-253 on MYC expression and its downstream target genes, on cell-cycle arrest, DNA damage, and stress responses can be explained by the action of Fe(253)3 and APTO-253 on G-quadruplex DNA motifs. Mol Cancer Ther; 17(6); 1177–86. ©2018 AACR.</jats:p> |
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| imprint_str_mv | American Association for Cancer Research (AACR), 2018 |
| institution | DE-Rs1, DE-Pl11, DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15 |
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| spelling | Local, Andrea Zhang, Hongying Benbatoul, Khalid D. Folger, Peter Sheng, Xia Tsai, Cheng-Yu Howell, Stephen B. Rice, William G. 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-17-1209 <jats:title>Abstract</jats:title> <jats:p>APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G0–G1 cell-cycle arrest, and triggers apoptosis in acute myeloid leukemia (AML) cells without producing myelosuppression in various animal species and humans. Differential gene expression analysis identified a pharmacodynamic effect on MYC expression, as well as induction of DNA repair and stress response pathways. APTO-253 was found to elicit a concentration- and time-dependent reduction in MYC mRNA expression and protein levels. Gene ontogeny and structural informatic analyses suggested a mechanism involving G-quadruplex (G4) stabilization. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)3]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253)3 stabilize G4 structures from telomeres, MYC, and KIT promoters but do not bind to non-G4 double-stranded DNA. Although APTO-253 exerts a host of mechanistic sequelae, the effect of APTO-253 on MYC expression and its downstream target genes, on cell-cycle arrest, DNA damage, and stress responses can be explained by the action of Fe(253)3 and APTO-253 on G-quadruplex DNA motifs. Mol Cancer Ther; 17(6); 1177–86. ©2018 AACR.</jats:p> APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells Molecular Cancer Therapeutics |
| spellingShingle | Local, Andrea, Zhang, Hongying, Benbatoul, Khalid D., Folger, Peter, Sheng, Xia, Tsai, Cheng-Yu, Howell, Stephen B., Rice, William G., Molecular Cancer Therapeutics, APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells, Cancer Research, Oncology |
| title | APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_full | APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_fullStr | APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_full_unstemmed | APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_short | APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| title_sort | apto-253 stabilizes g-quadruplex dna, inhibits myc expression, and induces dna damage in acute myeloid leukemia cells |
| title_unstemmed | APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1535-7163.mct-17-1209 |