Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an antiangina drug perhexiline.
Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an antiangina drug perhexiline.
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通过抗心绞痛药物 perhexiline 靶向 CPT 消除基质微环境中的慢性淋巴细胞白血病细胞
作者：
慢性淋巴细胞白血病（CLL）是西方国家最常见的成人白血病，目前无法治愈，部分原因是难以清除受基质微环境保护的白血病细胞。基于CLL细胞表现出线粒体功能障碍和脂质代谢改变以及肉毒碱棕榈酰转移酶（CPT）在将脂肪酸转运到线粒体中以支持癌细胞代谢中起主要作用的先前观察，我们测试了几种临床相关的脂质代谢抑制剂消除原发性CLL细胞的能力。我们发现，Perhexiline，一种抑制CPT的抗心绞痛药物，在临床可达到的浓度下，在杀死基质微环境中的CLL细胞方面非常有效。这些有效浓度对正常淋巴细胞和正常基质细胞产生低毒性。机制研究表明，CLL细胞表达高水平的CPT 1和CPT 2。通过使用Perhexiline抑制CPT来抑制脂肪酸转运到线粒体中，导致心磷脂（线粒体膜的关键成分）耗尽，并损害线粒体完整性，导致快速去极化和大规模CLL细胞死亡。使用CLL转基因小鼠模型在体内进一步证明了Perhexiline的治疗活性。仅通过4次药物注射，Perhexiline显著延长了动物的总体生存期。我们的研究表明，使用抗心绞痛药物靶向CPT能够有效地清除体内白血病细胞，并且是潜在的临床治疗CLL的新治疗策略。
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.
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