Wang Jiangwei, Su Xiaolin, Jiang Lingxiang, Boudreau Matthew W, Chatkewitz Lindsay E, Kilgore Jessica A, Zahid Kashif Rafiq, Williams Noelle S, Chen Yaomin, Liu Shaohui, Hergenrother Paul J, Huang Xiumei
Department of Radiation Oncology, Indianapolis, IN 46202, USA.
Department of Biochemistry and Molecular Biology, Indianapolis, IN 46202, USA.
Cancers (Basel). 2023 Dec 14;15(24):5844. doi: 10.3390/cancers15245844.
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 in NSCLC and breast cancer cells.
肺癌和乳腺癌是两种最常见且致命的肿瘤，在全球范围内导致了大量与癌症相关的死亡。尽管在过去二十年中肿瘤治疗取得了令人瞩目的进展，但开发靶向肿瘤治疗方法仍然面临重大挑战。NAD(P)H醌氧化还原酶1（NQO1）是一种双电子还原酶，据报道是多种实体瘤中有前景的治疗靶点。β-拉帕醌（β-Lap）和脱氧尼博醌（DNQ）是两种已显示出强大抗肿瘤作用的NQO1生物可激活药物。然而，它们的疗效受到副作用和中等致死率的限制。为了提高NQO1生物可激活药物的治疗潜力，我们开发了一种新型的DNQ衍生物，称为异戊基-脱氧尼博醌（IP-DNQ）。我们的研究表明，IP-DNQ处理显著增加了活性氧的产生，导致双链断裂（DSB）形成、PARP1过度激活和灾难性的能量损失。值得注意的是，我们发现这种新型药物诱导了细胞凋亡和程序性坏死事件，这使其与其他NQO1生物可激活药物完全不同。此外，在A549原位异种移植模型中，IP-DNQ单药治疗显示出显著的抗肿瘤疗效并延长了小鼠的生存期。最后，我们发现与IB-DNQ水平相比，小鼠血浆和肿瘤中的IP-DNQ水平显著升高。这项研究提供了新的临床前证据，支持IP-DNQ在非小细胞肺癌和乳腺癌细胞中的疗效。
