Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline
| العنوان: | Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline |
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| المؤلفون: | Jennifer S. Carew, Helene Pelicano, Wen-qi Jiang, Zeev Estrov, Pan-pan Liu, Jinyun Liu, Michael J. Keating, Peng Huang, Rui-Hua Xu, Carlo M. Croce, Marcia A. Ogasawara |
| المصدر: | Oncogene |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Chronic lymphocytic leukemia, Gene Expression, Pharmacology, chemistry.chemical_compound, Mice, 0302 clinical medicine, hemic and lymphatic diseases, Cardiolipin, Tumor Microenvironment, Mice, Knockout, Mitochondria, Leukemia, 030220 oncology & carcinogenesis, Perhexiline, Mitochondrial Membranes, medicine.drug, Stromal cell, Cardiolipins, Cell Survival, Antineoplastic Agents, Biology, Models, Biological, Article, Cell Line, stromal microenvironment, 03 medical and health sciences, Oxygen Consumption, Genetics, medicine, Animals, Humans, Molecular Biology, neoplasms, Tumor microenvironment, Carnitine O-Palmitoyltransferase, Lipid metabolism, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Xenograft Model Antitumor Assays, Disease Models, Animal, 030104 developmental biology, Glucose, chemistry, Cancer cell, CPT, Stromal Cells |
| الوصف: | Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western countries and is currently incurable due, in part, to difficulty in eliminating the leukemia cells protected by stromal microenvironment. Based on previous observations that CLL cells exhibit mitochondrial dysfunction and altered lipid metabolism and that carnitine palmitoyltransferases (CPT) have a major role in transporting fatty acid into mitochondria to support cancer cell metabolism, we tested several clinically relevant inhibitors of lipid metabolism for their ability to eliminate primary CLL cells. We discovered that perhexiline, an antiangina agent that inhibits CPT, was highly effective in killing CLL cells in stromal microenvironment at clinically achievable concentrations. These effective concentrations caused low toxicity to normal lymphocytes and normal stromal cells. Mechanistic study revealed that CLL cells expressed high levels of CPT1 and CPT2. Suppression of fatty acid transport into mitochondria by inhibiting CPT using perhexiline resulted in a depletion of cardiolipin, a key component of mitochondrial membranes, and compromised mitochondrial integrity, leading to rapid depolarization and massive CLL cell death. The therapeutic activity of perhexiline was further demonstrated in vivo using a CLL transgenic mouse model. Perhexiline significantly prolonged the overall animal survival by only four drug injections. Our study suggests that targeting CPT using an antiangina drug is able to effectively eliminate leukemia cells in vivo, and is a novel therapeutic strategy for potential clinical treatment of CLL. |
| اللغة: | English |
| تدمد: | 1476-5594 0950-9232 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6619ef3ce631c6726e2ad5e571b309f7Test http://europepmc.org/articles/PMC5064824Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6619ef3ce631c6726e2ad5e571b309f7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765594 09509232 |
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