Mitochondrial dysfunction is a hallmark of cancer cells and targeting cancer mitochondria has emerged as a promising anti‐cancer therapy. Previously, we repurposed chlorambucil by conjugating it to a mitochondrial targeting triphenylphosphonium (TPP) group to design Mito‐Chlor, a novel agent that acts on mitochondria DNA (mtDNA). Herein, we show that Mito‐Chlor, but not chlorambucil, inhibits the nascent transcription of mtDNA. Clustering analysis of transcriptomic profile of our Bru‐seq database led to the identification of another mitochondrial transcription inhibitor SQD1, which inhibits the proliferation of MIA PaCa‐2 cells with an IC₅₀ of 1.3 μM. Interestingly, Mito‐Chlor reduces expression of mitochondrial proteins, interferes with mitochondria membrane potential, and impairs oxidative phosphorylation while SQD1 does not. Both compounds increased cellular and mitochondrial reactive oxygen species and stimulated similar signaling pathways in response to oxidative stress. As mitochondrial transcription inhibitors and redox modulators, SQD1 and Mito‐Chlor are promising for the treatment of pancreatic cancer by blocking mitochondrial function.

中文翻译：

---

发现在胰腺癌细胞中有活性的线粒体转录抑制剂。

线粒体功能障碍是癌细胞的标志，靶向癌症线粒体已成为一种有前途的抗癌疗法。以前，我们通过将苯丁酸氮芥与靶向三苯基磷 (TPP) 的线粒体结合来重新利用苯丁酸氮芥，以设计 Mito-Chlor，这是一种作用于线粒体 DNA (mtDNA) 的新型药物。在此，我们表明 Mito-Chlor 而非苯丁酸氮芥可抑制 mtDNA 的新生转录。我们 Bru-seq 数据库转录组谱的聚类分析导致鉴定了另一种线粒体转录抑制剂 SQD1，其抑制 MIA PaCa-2 细胞的增殖，IC ₅₀1.3 μM。有趣的是，Mito-Chlor 会降低线粒体蛋白的表达，干扰线粒体膜电位，并损害氧化磷酸化，而 SQD1 则不会。这两种化合物都增加了细胞和线粒体的活性氧种类，并刺激了类似的信号通路以响应氧化应激。作为线粒体转录抑制剂和氧化还原调节剂，SQD1 和 Mito-Chlor 有望通过阻断线粒体功能来治疗胰腺癌。