Combination of Ethacrynic Acid and ATRA Triggers Differentiation and/or Apoptosis of Acute Myeloid Leukemia Cells through ROS
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
BACKGROUND AND OBJECTIVE: All-trans retinoic acid (ATRA), an effective differentiation inducer, has been applied clinically to treat acute promyelocytic leukemia (APL). Unfortunately, it is not as potent in other kinds of acute myeloid leukemia (AML). Ethacrynic acid (EA), a classical powerful diuretic, can increase reactive oxygen species (ROS) contents, which can assist ATRA in inducing differentiation in AML cells. Here, we investigated the effect of EA combined with ATRA (EA+RA) on some AML cells except APL.
METHODS: Apoptosis and differentiation were determined by morphology, cell viability, Annexin-V assay and CD11c expression. Western blot analysis and the detection of ROS and mitochondrial transmembrane potentials (MMP) were used to investigate the mechanisms.
RESULTS: AML cells exhibited differentiation and/or apoptosis after EA+RA treatment. EA+RA increased the intracellular ROS contents. EA+RA-induced apoptosis was accompanied by MMP attenuation and caspase-3/7 activation. EA+RA-induced differentiation was along with MEK/ERK and Akt activation and increased expression of PU.1, CCAAT/enhancer-binding protein β (C/EBPβ) and C/EBPε. N-acetyl-L-cysteine (NAC), an antioxidant, thoroughly reduced EA+RA-increased ROS, and also inhibited MMP attenuation, the activation of caspase- 3/7, MEK/ERK and Akt pathways, the elevation of PU.1 and C/EBPs, and apoptosis and differentiation. However, MEK or PI3K specific inhibitors only suppressed EA+RA-triggered differentiation and the elevation of PU.1 and C/EBPs, but not ROS levels.
CONCLUSION: EA+ATRA induced cell apoptosis through ROS dependent MMP attenuation and caspase 3/7 activation while inducing differentiation by ROS-MEK/ERK-PU.1/C/EBPs and ROS-Akt-PU.1/C/EBPs pathways. In summary, it may provide innovative ATRA-based combination therapy strategies for AML patients via ROS.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
Anti-cancer agents in medicinal chemistry - (2024) vom: 09. Jan. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Li, Lu [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Acute myeloid leukemia |
|---|
| Anmerkungen: |
Date Revised 11.01.2024 published: Print-Electronic Citation Status Publisher |
|---|
| doi: |
10.2174/0118715206273000231211092743 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM366948504 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM366948504 | ||
| 003 | DE-627 | ||
| 005 | 20240114234105.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240114s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.2174/0118715206273000231211092743 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1256.xml |
| 035 | |a (DE-627)NLM366948504 | ||
| 035 | |a (NLM)38204257 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Li, Lu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Combination of Ethacrynic Acid and ATRA Triggers Differentiation and/or Apoptosis of Acute Myeloid Leukemia Cells through ROS |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 11.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a BACKGROUND AND OBJECTIVE: All-trans retinoic acid (ATRA), an effective differentiation inducer, has been applied clinically to treat acute promyelocytic leukemia (APL). Unfortunately, it is not as potent in other kinds of acute myeloid leukemia (AML). Ethacrynic acid (EA), a classical powerful diuretic, can increase reactive oxygen species (ROS) contents, which can assist ATRA in inducing differentiation in AML cells. Here, we investigated the effect of EA combined with ATRA (EA+RA) on some AML cells except APL | ||
| 520 | |a METHODS: Apoptosis and differentiation were determined by morphology, cell viability, Annexin-V assay and CD11c expression. Western blot analysis and the detection of ROS and mitochondrial transmembrane potentials (MMP) were used to investigate the mechanisms | ||
| 520 | |a RESULTS: AML cells exhibited differentiation and/or apoptosis after EA+RA treatment. EA+RA increased the intracellular ROS contents. EA+RA-induced apoptosis was accompanied by MMP attenuation and caspase-3/7 activation. EA+RA-induced differentiation was along with MEK/ERK and Akt activation and increased expression of PU.1, CCAAT/enhancer-binding protein β (C/EBPβ) and C/EBPε. N-acetyl-L-cysteine (NAC), an antioxidant, thoroughly reduced EA+RA-increased ROS, and also inhibited MMP attenuation, the activation of caspase- 3/7, MEK/ERK and Akt pathways, the elevation of PU.1 and C/EBPs, and apoptosis and differentiation. However, MEK or PI3K specific inhibitors only suppressed EA+RA-triggered differentiation and the elevation of PU.1 and C/EBPs, but not ROS levels | ||
| 520 | |a CONCLUSION: EA+ATRA induced cell apoptosis through ROS dependent MMP attenuation and caspase 3/7 activation while inducing differentiation by ROS-MEK/ERK-PU.1/C/EBPs and ROS-Akt-PU.1/C/EBPs pathways. In summary, it may provide innovative ATRA-based combination therapy strategies for AML patients via ROS | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a All-trans retinoic acid | |
| 650 | 4 | |a acute myeloid leukemia | |
| 650 | 4 | |a apoptosis | |
| 650 | 4 | |a differentiation. | |
| 650 | 4 | |a ethacrynic acid | |
| 650 | 4 | |a reactive oxygen species | |
| 700 | 1 | |a Xi, Hui-Min |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Xun |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Anti-cancer agents in medicinal chemistry |d 2006 |g (2024) vom: 09. Jan. |w (DE-627)NLM160693403 |x 1875-5992 |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:09 |g month:01 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.2174/0118715206273000231211092743 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 09 |c 01 | ||