Lung and breast cancers rank as two of the most common and lethal tumors, accounting for a substantial number of cancer-related deaths worldwide. While the past two decades have witnessed promising progress in tumor therapy, developing targeted tumor therapies continues to pose a significant challenge. NAD(P)H quinone oxidoreductase 1 (NQO1), a two-electron reductase, has been reported as a promising therapeutic target across various solid tumors. β-Lapachone (β-Lap) and deoxynyboquinone (DNQ) are two NQO1 bioactivatable drugs that have demonstrated potent antitumor effects. However, their curative efficacy has been constrained by adverse effects and moderate lethality. To enhance the curative potential of NQO1 bioactivatable drugs, we developed a novel DNQ derivative termed isopentyl-deoxynyboquinone (IP-DNQ). Our study revealed that IP-DNQ treatment significantly increased reactive oxygen species generation, leading to double-strand break (DSB) formation, PARP1 hyperactivation, and catastrophic energy loss. Notably, we discovered that this novel drug induced both apoptosis and programmed necrosis events, which makes it entirely distinct from other NQO1 bioactivatable drugs. Furthermore, IP-DNQ monotherapy demonstrated significant antitumor efficacy and extended mice survival in A549 orthotopic xenograft models. Lastly, we identified that in mice IP-DNQ levels were significantly elevated in the plasma and tumor compared with IB-DNQ levels. This study provides novel preclinical evidence supporting IP-DNQ efficacy inNQO1+NSCLC and breast cancer cells.
肺癌与乳腺癌是两种最为常见且致死率极高的恶性肿瘤，在全球范围内导致大量癌症相关死亡。尽管过去二十年间肿瘤治疗领域取得了显著进展，但开发靶向肿瘤疗法仍面临重大挑战。NAD(P)H醌氧化还原酶1（NQO1）作为一种双电子还原酶，已被报道在多种实体瘤中具有成为治疗靶点的潜力。β-拉帕醌（β-Lap）与脱氧尼波醌（DNQ）是两种NQO1生物可激活药物，已展现出强大的抗肿瘤效果。然而，其疗效受限于不良反应及中等程度的杀伤效力。为提升NQO1生物可激活药物的治疗潜力，我们开发了一种新型DNQ衍生物——异戊基-脱氧尼波醌（IP-DNQ）。研究发现，IP-DNQ处理能显著增加活性氧生成，进而导致DNA双链断裂形成、PARP1过度活化及灾难性能量耗竭。值得注意的是，该新型药物可同时诱导细胞凋亡与程序性坏死，这使其与其他NQO1生物可激活药物存在本质区别。此外，在A549原位移植瘤模型中，IP-DNQ单药治疗显示出显著的抗肿瘤效果并延长了小鼠生存期。最后，我们发现在小鼠体内IP-DNQ的血浆与肿瘤浓度均显著高于IB-DNQ。本研究为IP-DNQ在NQO1阳性非小细胞肺癌与乳腺癌细胞中的疗效提供了新的临床前证据。
肿瘤(癌症)患者之家