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| Content Provider | frontiers |
|---|---|
| Author | 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, Dhananjaya Bhojwani, Deepa Durden, Donald L. Kim, Yong-Mi |
| Abstract | The PI3K/Akt pathwayand in particular PI3Kδis 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. 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 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, adhesion molecules expression using both 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. |
| ISSN | 2234943X |
| DOI | 10.3389/fonc.2021.766888 |
| Volume Number | 11 |
| Journal | Frontiers in Oncology |
| Language | English |
| Publisher Date | 2021-12-01 |
| Access Restriction | Open |
| Subject Keyword | PI3Kδ BRD4 Acute Lymphoblastic Leukemia SF2535 C-Myc P-AKT |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cancer Research Oncology |
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