JNCI：抑制肉碱乙酰基转移酶可预防Myc诱导的淋巴瘤生成

我们可根据肿瘤细胞的代谢选择来研发选择性抗肿瘤治疗方案。ST1326是一种肉碱乙酰基转移酶1A抑制剂，能将脂肪酸导入到线粒体内的限速酶。来自意大利di Bologna大学的Annalisa Pacilli等为了探究ST1236对肿瘤的治疗潜能而设计了相关研究，他们的研究结果发表在JNCI 4月最新的在线期刊上。

研究者在Burkitt淋巴瘤的体外模型和体内模型中对ST1326进行了测评，他们发现在体内外模型中c-myc的过度表达，c-myc能增加细胞对脂肪酸代谢的需求。在Raji细胞中评估了ST1326对细胞增殖、脂肪酸氧化和脂肪酸线粒体通道的影响。研究者采用经Eμ-myc治疗的小鼠模型来评估ST1326的治疗价值（对照组29只小鼠，治疗组24只小鼠），以及建立了c-myc介导的淋巴瘤模型。研究者在过度表达c-myc的脾源性B细胞中进行了研究，以确定c-myc对ST1326所造成的影响。研究者采用Kaplan-Meier分析评估生存期等相关信息。所有的统计检验都在双侧进行。

ST-1326能阻滞长链脂肪酸和短链脂肪酸氧化，在Burkkitt’淋巴瘤中表现出较强的细胞毒效应（在Raji细胞中72小时最大半数抑制浓度为8.6 μM）。ST1326治疗能诱导胞浆脂质的大量积聚、线粒体脂肪酸通道的功能障碍，以及胞质乙酰辅酶A（脂肪从头合成的基本物质）可用性降低。此外，将ST1326用于Eμ-myc转基因小鼠的治疗能通过选择性破坏过度表达c-myc的脾源性初级B细胞来预防肿瘤形成。

本研究结果指出，可通过改变脂质代谢和肿瘤细胞所需要的脂肪酸氧化来预防c-myc诱导的肿瘤的形成。

与淋巴瘤相关的拓展阅读：

• NEJM:利妥昔单抗治疗纵隔淋巴瘤可避免放疗
• NEJM：利妥昔单抗方案治疗纵隔B细胞淋巴瘤可避免放疗
• JCO:ABVD标准治疗方案不适用于老年霍奇金淋巴瘤
• Blood：红斑狼疮治疗药不增加淋巴瘤风险
• NEJM：霍奇金淋巴瘤患儿药物短缺不容小觑
• Mol Cell Biol：鉴别淋巴瘤突变的好坏
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Carnitine-Acyltransferase System Inhibition, Cancer Cell Death, and Prevention of Myc-Induced Lymphomagenesis
Background
The metabolic alterations of cancer cells represent an opportunity for developing selective antineoplastic treatments. We investigated the therapeutic potential of ST1326, an inhibitor of carnitine-palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme for fatty acid (FA) import into mitochondria.
Methods
ST1326 was tested on in vitro and in vivo models of Burkitt’s lymphoma, in which c-myc, which drives cellular demand for FA metabolism, is highly overexpressed. We performed assays to evaluate the effect of ST1326 on proliferation, FA oxidation, and FA mitochondrial channeling in Raji cells. The therapeutic efficacy of ST1326 was tested by treating Eµ-myc mice (control: n = 29; treatment: n = 24 per group), an established model of c-myc–mediated lymphomagenesis. Experiments were performed on spleen-derived c-myc–overexpressing B cells to clarify the role of c-myc in conferring sensitivity to ST1326. Survival was evaluated with Kaplan–Meier analyses. All statistical tests were two-sided.
Results
ST1326 blocked both long- and short-chain FA oxidation and showed a strong cytotoxic effect on Burkitt’s lymphoma cells (on Raji cells at 72 hours: half maximal inhibitory concentration = 8.6 μM). ST1326 treatment induced massive cytoplasmic lipid accumulation, impairment of proper mitochondrial FA channeling, and reduced availability of cytosolic acetyl coenzyme A, a fundamental substrate for de novo lipogenesis. Moreover, treatment with ST1326 in Eµ-myc transgenic mice prevented tumor formation (P = .01), by selectively impairing the growth of spleen-derived primary B cells overexpressing c-myc (wild-type cells + ST1326 vs Eµ-myc cells + ST1326: 99.75% vs 57.5%, difference = 42.25, 95% confidence interval of difference = 14% to 70%; P = .01).
Conclusions
Our data indicate that it is possible to tackle c-myc–driven tumorigenesis by altering lipid metabolism and exploiting the neoplastic cell addiction to FA oxidation.