دورية أكاديمية
A Selective Novel Peroxisome Proliferator-Activated Receptor ( PPAR)-alpha Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo
| العنوان: | A Selective Novel Peroxisome Proliferator-Activated Receptor ( PPAR)-alpha Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo |
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| المؤلفون: | Messmer, D., Lorrain, K., Stebbins, K., Bravo, Y., Stock, N., Cabrera, G., Correa, L., Chiorazzi, N., Yan, X. J., Lorrain, D., +4 additional authors |
| المصدر: | Journal Articles |
| بيانات النشر: | Donald and Barbara Zucker School of Medicine Academic Works |
| سنة النشر: | 2015 |
| المجموعة: | Hofstra Northwell Academic Works (Hofstra Northwell School of Medicine) |
| مصطلحات موضوعية: | chronic lymphocytic-leukemia, fatty-acid oxidation, ppar-alpha, b-cells, breast-cancer, tumor-growth, induction, chemokine, survival, microenvironment, Biochemistry & Molecular Biology, Cell Biology, Research & Experimental, Medicine, Medical Molecular Biology |
| الوصف: | Tumor-specific metabolic changes can reveal new therapeutic targets. Our findings implicate a supporting role for fatty acid metabolism in chronic lymphocytic leukemia (CLL) cell survival. Peroxisome proliferator-activated receptor (PPAR)-alpha, a major transcriptional regulator of fatty acid oxidation, was recently shown to be upregulated in CLL. To evaluate PPAR alpha as a potential therapeutic target, we developed a highly selective, potent small molecule antagonist of PPAR alpha, NXT629. NXT629 inhibited agonist-induced transcription of PPAR alpha-regulated genes, demonstrating target engagement in CLL cells. Furthermore, NXT629 induced apoptosis of CLL cells even in the presence of a protective microenvironment. To mimic the proliferative lymphoid compartment of CLL, we examined the activity of NXT629 on CLL cells that were stimulated to proliferate in vitro. NXT629 reduced the number of leukemia cells undergoing cell division. In addition, in two xenograft mouse models of CLL (one a model for nondividing and one for dividing CLL), NXT629 reduced the number of viable CLL cells in vivo. Overall, these results suggest that fatty acid metabolism promotes survival and proliferation of primary CLL cells and that inhibiting PPAR alpha gene regulation could be a new therapeutic approach to treating CLL. |
| نوع الوثيقة: | text |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| العلاقة: | https://academicworks.medicine.hofstra.edu/publications/2962Test; https://academicworks.medicine.hofstra.edu/context/publications/article/3963/viewcontent/MolMed2015v21p410.pdfTest |
| DOI: | 10.2119/molmed.2015.00139 |
| الإتاحة: | https://doi.org/10.2119/molmed.2015.00139Test https://academicworks.medicine.hofstra.edu/publications/2962Test https://academicworks.medicine.hofstra.edu/context/publications/article/3963/viewcontent/MolMed2015v21p410.pdfTest |
| رقم الانضمام: | edsbas.29D5615E |
| قاعدة البيانات: | BASE |
| DOI: | 10.2119/molmed.2015.00139 |
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