Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms.
Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms.
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DOI：
10.3390/cancers15245844
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发表时间：
2023-12-14
期刊：
影响因子：
5.2
通讯作者：
Huang, Xiumei
中科院分区：
文献类型：
--
作者：
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
尽管化疗仍然是多种人类肿瘤的基本治疗方法，但化疗耐药性的出现是肿瘤治疗的主要障碍。因此，鉴定新的化疗药物对于克服这一限制和开发更有效的肿瘤治疗至关重要。在这项研究中，我们证明了一种新的NQO1生物激活药物IP-DNQ通过诱导凋亡和程序性坏死有效地根除NQO1阳性癌细胞，与之前测试的NQO1生物激活药物相比，显示出显著的抗肿瘤潜力。在机制上，IP-DNQ通过产生过多的活性氧（ROS）来消灭nqo1阳性的癌细胞，从而诱导DNA损伤、PARP1过度激活和灾难性的能量损失。总之，本研究展示了IP-DNQ对nqo1阳性癌细胞令人难以置信的抗肿瘤功效。肺癌和乳腺癌是最常见和最致命的两种肿瘤，在全世界与癌症相关的死亡中占相当大的比例。虽然在过去的二十年中，肿瘤治疗取得了可喜的进展，但开发靶向肿瘤治疗仍然是一个重大挑战。NAD(P)H醌氧化还原酶1 （NQO1）是一种双电子还原酶，已被报道为多种实体肿瘤的治疗靶点。β-Lapachone （β-Lap）和脱氧波醌（DNQ）是两种具有NQO1生物活化作用的抗肿瘤药物。然而，其疗效一直受到不良反应和中等致死率的限制。为了提高NQO1生物活化药物的治疗潜力，我们开发了一种新的DNQ衍生物，称为异戊基-脱氧氨基醌（IP-DNQ）。我们的研究表明，IP-DNQ处理显著增加活性氧的产生，导致双链断裂（DSB）的形成，PARP1的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可诱导细胞凋亡和程序性坏死事件，这使其与其他NQO1生物激活药物完全不同。此外，IP-DNQ单药治疗在A549原位异种移植模型中显示出显著的抗肿瘤疗效和延长小鼠生存期。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。本研究提供了新的临床前证据，支持IP-DNQ对nq01 + NSCLC和乳腺癌细胞的疗效。
Although chemotherapy remains a fundamental treatment for a wide variety of human tumors, the emergence of resistance to chemotherapy presents a major hurdle in tumor therapy. Therefore, the identification of novel chemotherapeutic agents is essential to overcome this limitation and develop more effective tumor therapies. In this study, we illustrate that a novel NQO1 bioactivatable drug, IP-DNQ, effectively eradicates NQO1-positive cancer cells by inducing both apoptosis and programmed necrosis, displaying remarkable antitumor potential compared with previously tested NQO1 bioactivatable drugs. Mechanistically, IP-DNQ exterminates NQO1-positive cancer cells by generating excessive reactive oxygen species (ROS), thereby inducing DNA damage, PARP1 hyperactivation, and catastrophic energy loss. Overall, this study showcases the incredible antitumor efficacy of IP-DNQ against NQO1-positive cancer cells. 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 NQO1+ NSCLC and breast cancer cells.
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影响因子：
4.7
作者：
Shukla K;Singh N;Lewis JE;Tsang AW;Boothman DA;Kemp ML;Furdui CM
通讯作者：
Furdui CM
DOI：
10.1016/j.neo.2021.06.008
发表时间：
2021-08
期刊：
Neoplasia (New York, N.Y.)
影响因子：
--
作者：
Lundberg AP;Boudreau MW;Selting KA;Chatkewitz LE;Samuelson J;Francis JM;Parkinson EI;Barger AM;Hergenrother PJ;Fan TM
通讯作者：
Fan TM
影响因子：
10
作者：
Ma, Xinpeng;Huang, Xiumei;Huang, Gang;Li, Longshan;Wang, Yiguang;Luo, Xiuquan;Boothman, David A.;Gao, Jinming
通讯作者：
Gao, Jinming
过氧化氢酶消除了NQO1阳性乳腺癌中的β-拉帕酮诱导的PARP1过度激活导向的坏死。
影响因子：
5.7
作者：
Bey EA;Reinicke KE;Srougi MC;Varnes M;Anderson VE;Pink JJ;Li LS;Patel M;Cao L;Moore Z;Rommel A;Boatman M;Lewis C;Euhus DM;Bornmann WG;Buchsbaum DJ;Spitz DR;Gao J;Boothman DA
通讯作者：
Boothman DA
影响因子：
50.3
作者：
Huang X;Motea EA;Moore ZR;Yao J;Dong Y;Chakrabarti G;Kilgore JA;Silvers MA;Patidar PL;Cholka A;Fattah F;Cha Y;Anderson GG;Kusko R;Peyton M;Yan J;Xie XJ;Sarode V;Williams NS;Minna JD;Beg M;Gerber DE;Bey EA;Boothman DA
通讯作者：
Boothman DA