Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia

Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of ant...
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Gespeichert in:

Autor*in:	Pierre-Luc Mouchel [verfasserIn] Nizar Serhan [verfasserIn] Rémy Betous [verfasserIn] Thomas Farge [verfasserIn] Estelle Saland [verfasserIn] Philippe De Medina [verfasserIn] Jean-Sébastien Hoffmann [verfasserIn] Jean-Emmanuel Sarry [verfasserIn] Marc Poirot [verfasserIn] Sandrine Silvente-Poirot [verfasserIn] Christian Récher [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	AML LXR dendrogenin A DDA anthracycline synergy

Übergeordnetes Werk:	In: Cancers - MDPI AG, 2010, 12(2020), 10, p 2933
Übergeordnetes Werk:	volume:12 ; year:2020 ; number:10, p 2933

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/cancers12102933

Katalog-ID:	DOAJ052905500

Internformat


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520			\|a Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients.
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allfields	10.3390/cancers12102933 doi (DE-627)DOAJ052905500 (DE-599)DOAJ6035e7e043fe4cde9c26328b0937901e DE-627 ger DE-627 rakwb eng RC254-282 Pierre-Luc Mouchel verfasserin aut Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients. AML LXR dendrogenin A DDA anthracycline synergy Neoplasms. Tumors. Oncology. Including cancer and carcinogens Nizar Serhan verfasserin aut Rémy Betous verfasserin aut Thomas Farge verfasserin aut Estelle Saland verfasserin aut Philippe De Medina verfasserin aut Jean-Sébastien Hoffmann verfasserin aut Jean-Emmanuel Sarry verfasserin aut Marc Poirot verfasserin aut Sandrine Silvente-Poirot verfasserin aut Christian Récher verfasserin aut In Cancers MDPI AG, 2010 12(2020), 10, p 2933 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:12 year:2020 number:10, p 2933 https://doi.org/10.3390/cancers12102933 kostenfrei https://doaj.org/article/6035e7e043fe4cde9c26328b0937901e kostenfrei https://www.mdpi.com/2072-6694/12/10/2933 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 10, p 2933
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allfields_unstemmed	10.3390/cancers12102933 doi (DE-627)DOAJ052905500 (DE-599)DOAJ6035e7e043fe4cde9c26328b0937901e DE-627 ger DE-627 rakwb eng RC254-282 Pierre-Luc Mouchel verfasserin aut Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients. AML LXR dendrogenin A DDA anthracycline synergy Neoplasms. Tumors. Oncology. Including cancer and carcinogens Nizar Serhan verfasserin aut Rémy Betous verfasserin aut Thomas Farge verfasserin aut Estelle Saland verfasserin aut Philippe De Medina verfasserin aut Jean-Sébastien Hoffmann verfasserin aut Jean-Emmanuel Sarry verfasserin aut Marc Poirot verfasserin aut Sandrine Silvente-Poirot verfasserin aut Christian Récher verfasserin aut In Cancers MDPI AG, 2010 12(2020), 10, p 2933 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:12 year:2020 number:10, p 2933 https://doi.org/10.3390/cancers12102933 kostenfrei https://doaj.org/article/6035e7e043fe4cde9c26328b0937901e kostenfrei https://www.mdpi.com/2072-6694/12/10/2933 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 10, p 2933
allfieldsGer	10.3390/cancers12102933 doi (DE-627)DOAJ052905500 (DE-599)DOAJ6035e7e043fe4cde9c26328b0937901e DE-627 ger DE-627 rakwb eng RC254-282 Pierre-Luc Mouchel verfasserin aut Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients. AML LXR dendrogenin A DDA anthracycline synergy Neoplasms. Tumors. Oncology. Including cancer and carcinogens Nizar Serhan verfasserin aut Rémy Betous verfasserin aut Thomas Farge verfasserin aut Estelle Saland verfasserin aut Philippe De Medina verfasserin aut Jean-Sébastien Hoffmann verfasserin aut Jean-Emmanuel Sarry verfasserin aut Marc Poirot verfasserin aut Sandrine Silvente-Poirot verfasserin aut Christian Récher verfasserin aut In Cancers MDPI AG, 2010 12(2020), 10, p 2933 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:12 year:2020 number:10, p 2933 https://doi.org/10.3390/cancers12102933 kostenfrei https://doaj.org/article/6035e7e043fe4cde9c26328b0937901e kostenfrei https://www.mdpi.com/2072-6694/12/10/2933 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 10, p 2933
allfieldsSound	10.3390/cancers12102933 doi (DE-627)DOAJ052905500 (DE-599)DOAJ6035e7e043fe4cde9c26328b0937901e DE-627 ger DE-627 rakwb eng RC254-282 Pierre-Luc Mouchel verfasserin aut Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients. AML LXR dendrogenin A DDA anthracycline synergy Neoplasms. Tumors. Oncology. Including cancer and carcinogens Nizar Serhan verfasserin aut Rémy Betous verfasserin aut Thomas Farge verfasserin aut Estelle Saland verfasserin aut Philippe De Medina verfasserin aut Jean-Sébastien Hoffmann verfasserin aut Jean-Emmanuel Sarry verfasserin aut Marc Poirot verfasserin aut Sandrine Silvente-Poirot verfasserin aut Christian Récher verfasserin aut In Cancers MDPI AG, 2010 12(2020), 10, p 2933 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:12 year:2020 number:10, p 2933 https://doi.org/10.3390/cancers12102933 kostenfrei https://doaj.org/article/6035e7e043fe4cde9c26328b0937901e kostenfrei https://www.mdpi.com/2072-6694/12/10/2933 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 10, p 2933
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authorswithroles_txt_mv	Pierre-Luc Mouchel @@aut@@ Nizar Serhan @@aut@@ Rémy Betous @@aut@@ Thomas Farge @@aut@@ Estelle Saland @@aut@@ Philippe De Medina @@aut@@ Jean-Sébastien Hoffmann @@aut@@ Jean-Emmanuel Sarry @@aut@@ Marc Poirot @@aut@@ Sandrine Silvente-Poirot @@aut@@ Christian Récher @@aut@@
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callnumber-first	R - Medicine
author	Pierre-Luc Mouchel
spellingShingle	Pierre-Luc Mouchel misc RC254-282 misc AML misc LXR misc dendrogenin A misc DDA misc anthracycline misc synergy misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia
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topic_title	RC254-282 Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia AML LXR dendrogenin A DDA anthracycline synergy
topic	misc RC254-282 misc AML misc LXR misc dendrogenin A misc DDA misc anthracycline misc synergy misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC254-282 misc AML misc LXR misc dendrogenin A misc DDA misc anthracycline misc synergy misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia
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title_full	Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia
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title_sort	dendrogenin a enhances anti-leukemic effect of anthracycline in acute myeloid leukemia
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title_auth	Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia
abstract	Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients.
abstractGer	Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients.
abstract_unstemmed	Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients.
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up_date	2024-07-03T14:43:14.574Z
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Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia

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