Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia

The PI3K/Akt pathway—and in particular PI3Kδ—is known for its role in drug resistant B-cell acute lymphoblastic leukemia (B-ALL) and it is often upregulated in refractory or relapsed B-ALL. Myc proteins are transcription factors responsible for transcribing pro-proliferative genes and c-Myc is often...

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Autores principales:	Yongsheng Ruan, Hye Na Kim, Heather A. Ogana, Zesheng Wan, Samantha Hurwitz, Cydney Nichols, Nour Abdel-Azim, Ariana Coba, Seyoung Seo, Yong-Hwee Eddie Loh, Eun Ji Gang, Hisham Abdel-Azim, Chih-Lin Hsieh, Michael R. Lieber, Chintan Parekh, Dhananjay Pal, Deepa Bhojwani, Donald L. Durden, Yong-Mi Kim
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	PI3Kδ p-AKT BRD4 c-Myc acute lymphoblastic leukemia SF2535 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/9d2a16f695cc4722b8574521dd391e56
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spelling	oai:doaj.org-article:9d2a16f695cc4722b8574521dd391e562021-12-01T21:41:19ZPreclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia2234-943X10.3389/fonc.2021.766888https://doaj.org/article/9d2a16f695cc4722b8574521dd391e562021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.766888/fullhttps://doaj.org/toc/2234-943XThe PI3K/Akt pathway—and in particular PI3Kδ—is known for its role in drug resistant B-cell acute lymphoblastic leukemia (B-ALL) and it is often upregulated in refractory or relapsed B-ALL. Myc proteins are transcription factors responsible for transcribing pro-proliferative genes and c-Myc is often overexpressed in cancers. The chromatin regulator BRD4 is required for expression of c-Myc in hematologic malignancies including B-ALL. Previously, combination of BRD4 and PI3K inhibition with SF2523 was shown to successfully decrease Myc expression. However, the underlying mechanism and effect of dual inhibition of PI3Kδ/BRD4 in B-ALL remains unknown. To study this, we utilized SF2535, a novel small molecule dual inhibitor which can specifically target the PI3Kδ isoform and BRD4. We treated primary B-ALL cells with various concentrations of SF2535 and studied its effect on specific pharmacological on-target mechanisms such as apoptosis, cell cycle, cell proliferation, and adhesion molecules expression usingin vitro and in vivo models. SF2535 significantly downregulates both c-Myc mRNA and protein expression through inhibition of BRD4 at the c-Myc promoter site and decreases p-AKT expression through inhibition of the PI3Kδ/AKT pathway. SF2535 induced apoptosis in B-ALL by downregulation of BCL-2 and increased cleavage of caspase-3, caspase-7, and PARP. Moreover, SF2535 induced cell cycle arrest and decreased cell counts in B-ALL. Interestingly, SF2535 decreased the mean fluorescence intensity (MFI) of integrin α4, α5, α6, and β1 while increasing MFI of CXCR4, indicating that SF2535 may work through inside-out signaling of integrins. Taken together, our data provide a rationale for the clinical evaluation of targeting PI3Kδ/BRD4 in refractory or relapsed B-ALL using SF2535.Yongsheng RuanYongsheng RuanHye Na KimHeather A. OganaZesheng WanSamantha HurwitzCydney NicholsNour Abdel-AzimAriana CobaSeyoung SeoYong-Hwee Eddie LohEun Ji GangHisham Abdel-AzimChih-Lin HsiehMichael R. LieberChintan ParekhDhananjay PalDeepa BhojwaniDonald L. DurdenDonald L. DurdenYong-Mi KimFrontiers Media S.A.articlePI3Kδp-AKTBRD4c-Mycacute lymphoblastic leukemiaSF2535Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	PI3Kδ p-AKT BRD4 c-Myc acute lymphoblastic leukemia SF2535 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	PI3Kδ p-AKT BRD4 c-Myc acute lymphoblastic leukemia SF2535 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yongsheng Ruan Yongsheng Ruan Hye Na Kim Heather A. Ogana Zesheng Wan Samantha Hurwitz Cydney Nichols Nour Abdel-Azim Ariana Coba Seyoung Seo Yong-Hwee Eddie Loh Eun Ji Gang Hisham Abdel-Azim Chih-Lin Hsieh Michael R. Lieber Chintan Parekh Dhananjay Pal Deepa Bhojwani Donald L. Durden Donald L. Durden Yong-Mi Kim Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia
description	The PI3K/Akt pathway—and in particular PI3Kδ—is known for its role in drug resistant B-cell acute lymphoblastic leukemia (B-ALL) and it is often upregulated in refractory or relapsed B-ALL. Myc proteins are transcription factors responsible for transcribing pro-proliferative genes and c-Myc is often overexpressed in cancers. The chromatin regulator BRD4 is required for expression of c-Myc in hematologic malignancies including B-ALL. Previously, combination of BRD4 and PI3K inhibition with SF2523 was shown to successfully decrease Myc expression. However, the underlying mechanism and effect of dual inhibition of PI3Kδ/BRD4 in B-ALL remains unknown. To study this, we utilized SF2535, a novel small molecule dual inhibitor which can specifically target the PI3Kδ isoform and BRD4. We treated primary B-ALL cells with various concentrations of SF2535 and studied its effect on specific pharmacological on-target mechanisms such as apoptosis, cell cycle, cell proliferation, and adhesion molecules expression usingin vitro and in vivo models. SF2535 significantly downregulates both c-Myc mRNA and protein expression through inhibition of BRD4 at the c-Myc promoter site and decreases p-AKT expression through inhibition of the PI3Kδ/AKT pathway. SF2535 induced apoptosis in B-ALL by downregulation of BCL-2 and increased cleavage of caspase-3, caspase-7, and PARP. Moreover, SF2535 induced cell cycle arrest and decreased cell counts in B-ALL. Interestingly, SF2535 decreased the mean fluorescence intensity (MFI) of integrin α4, α5, α6, and β1 while increasing MFI of CXCR4, indicating that SF2535 may work through inside-out signaling of integrins. Taken together, our data provide a rationale for the clinical evaluation of targeting PI3Kδ/BRD4 in refractory or relapsed B-ALL using SF2535.
format	article
author	Yongsheng Ruan Yongsheng Ruan Hye Na Kim Heather A. Ogana Zesheng Wan Samantha Hurwitz Cydney Nichols Nour Abdel-Azim Ariana Coba Seyoung Seo Yong-Hwee Eddie Loh Eun Ji Gang Hisham Abdel-Azim Chih-Lin Hsieh Michael R. Lieber Chintan Parekh Dhananjay Pal Deepa Bhojwani Donald L. Durden Donald L. Durden Yong-Mi Kim
author_facet	Yongsheng Ruan Yongsheng Ruan Hye Na Kim Heather A. Ogana Zesheng Wan Samantha Hurwitz Cydney Nichols Nour Abdel-Azim Ariana Coba Seyoung Seo Yong-Hwee Eddie Loh Eun Ji Gang Hisham Abdel-Azim Chih-Lin Hsieh Michael R. Lieber Chintan Parekh Dhananjay Pal Deepa Bhojwani Donald L. Durden Donald L. Durden Yong-Mi Kim
author_sort	Yongsheng Ruan
title	Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia
title_short	Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia
title_full	Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia
title_fullStr	Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia
title_full_unstemmed	Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia
title_sort	preclinical evaluation of a novel dual targeting pi3kδ/brd4 inhibitor, sf2535, in b-cell acute lymphoblastic leukemia
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/9d2a16f695cc4722b8574521dd391e56
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Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia

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