Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline

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...

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Main Authors:	Liu, Pan-pan, Liu, Jinyun, Jiang, Wen-qi, Carew, Jennifer S., Ogasawara, Marcia A., Pelicano, Hélène, Croce, Carlo M., Estrov, Zeev, Xu, Rui-hua, Keating, Michael J., Huang, Peng
Format:	Online
Language:	English
Published:	2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064824/

id	pubmed-5064824
recordtype	oai_dc
spelling	pubmed-50648242016-10-28 Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline Liu, Pan-pan Liu, Jinyun Jiang, Wen-qi Carew, Jennifer S. Ogasawara, Marcia A. Pelicano, Hélène Croce, Carlo M. Estrov, Zeev Xu, Rui-hua Keating, Michael J. Huang, Peng Article 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) play 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 anti-angina 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 4 drug injections. Our study suggests that targeting CPT using an anti-angina drug is able to effectively eliminate leukemia cells in vivo, and is a novel therapeutic strategy for potential clinical treatment of CLL. 2016-04-11 2016-10-27 /pmc/articles/PMC5064824/ /pubmed/27065330 http://dx.doi.org/10.1038/onc.2016.103 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Liu, Pan-pan Liu, Jinyun Jiang, Wen-qi Carew, Jennifer S. Ogasawara, Marcia A. Pelicano, Hélène Croce, Carlo M. Estrov, Zeev Xu, Rui-hua Keating, Michael J. Huang, Peng
spellingShingle	Liu, Pan-pan Liu, Jinyun Jiang, Wen-qi Carew, Jennifer S. Ogasawara, Marcia A. Pelicano, Hélène Croce, Carlo M. Estrov, Zeev Xu, Rui-hua Keating, Michael J. Huang, Peng Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline
author_facet	Liu, Pan-pan Liu, Jinyun Jiang, Wen-qi Carew, Jennifer S. Ogasawara, Marcia A. Pelicano, Hélène Croce, Carlo M. Estrov, Zeev Xu, Rui-hua Keating, Michael J. Huang, Peng
author_sort	Liu, Pan-pan
title	Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline
title_short	Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline
title_full	Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline
title_fullStr	Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline
title_full_unstemmed	Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline
title_sort	elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting cpt with an anti-angina drug perhexiline
description	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) play 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 anti-angina 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 4 drug injections. Our study suggests that targeting CPT using an anti-angina drug is able to effectively eliminate leukemia cells in vivo, and is a novel therapeutic strategy for potential clinical treatment of CLL.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064824/
_version_	1613685000545239040

Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline

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