التفاصيل البيبلوغرافية
| العنوان: |
Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia. |
| المؤلفون: |
Ruan, Yongsheng, Kim, Hye Na, Ogana, Heather A., Wan, Zesheng, Hurwitz, Samantha, Nichols, Cydney, Abdel-Azim, Nour, Coba, Ariana, Seo, Seyoung, Loh, Yong-Hwee Eddie, Gang, Eun Ji, Abdel-Azim, Hisham, Hsieh, Chih-Lin, Lieber, Michael R., Parekh, Chintan, Pal, Dhananjay, Bhojwani, Deepa, Durden, Donald L., Kim, Yong-Mi |
| المصدر: |
Frontiers in Oncology; 12/1/2021, Vol. 11, p1-11, 11p |
| مصطلحات موضوعية: |
LYMPHOBLASTIC leukemia, ACUTE leukemia, SMALL molecules, GENE expression, PI3K/AKT pathway |
| مستخلص: |
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 using in 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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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