Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment.
Targeting CAR and Nrf2 improves cyclophosphamide bioactivation while reducing doxorubicin-induced cardiotoxicity in triple-negative breast cancer treatment.
复制标题
在三阴性乳腺癌治疗中，靶向 CAR 和 Nrf2 可改善环磷酰胺的生物活性，同时减少阿霉素诱导的心脏毒性。
DOI：
10.1172/jci.insight.153868
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发表时间：
2022
期刊：
影响因子：
8
通讯作者：
Wang,Hongbing
中科院分区：
文献类型：
--
作者：
Stern,Sydney;Liang,Dongdong;Li,Linhao;Kurian,Ritika;Lynch,Caitlin;Sakamuru,Srilatha;Heyward,Scott;Zhang,Junran;Kareem,KafayatAjoke;Chun,YoungWook;Huang,Ruili;Xia,Menghang;Hong,CharlesC;Xue,Fengtian;Wang,Hongbing
环磷酰胺 (CPA) 和阿霉素 (DOX) 是三阴性乳腺癌 (TNBC) 化疗的关键成分，尽管次优结果通常与耐药性和/或无法忍受的副作用有关。通过高通量筛选和化学修饰相结合的方法，我们开发了CN06作为组成型雄甾烷受体（CAR）和核因子红细胞2相关因子2（Nrf2）的双重激活剂。 CN06 通过激发 CYP2B6 的肝脏表达来增强 CAR 诱导的 CPA（前药）生物活性，同时通过刺激 Nrf2 抗氧化信号传导来抑制体外 DOX 诱导的心肌细胞细胞毒性。利用包含人原代肝细胞、TNBC 细胞和心肌细胞的多细胞共培养模型，我们发现 CN06 通过 CAR 依赖性 CYP2B6 诱导和随后 CPA 转化为其活性代谢物 4-羟基-CPA 增加 CPA/DOX 介导的 TNBC 细胞死亡，同时通过选择性激活心肌细胞中而非 TNBC 细胞中的 Nrf2 抗氧化信号来防止 DOX 诱导的心脏毒性。此外，CN06 通过调节抗氧化防御、减少细胞凋亡以及增强收缩和舒张动力学，保留人类 iPSC 衍生心肌细胞的活力和功能。总的来说，我们的研究结果将 CAR 和 Nrf2 确定为潜在的新型联合治疗靶点，其中 CN06 有可能提高含 CPA/DOX 化疗的疗效/毒性比。
Cyclophosphamide (CPA) and doxorubicin (DOX) are key components of chemotherapy for triple-negative breast cancer (TNBC), although suboptimal outcomes are commonly associated with drug resistance and/or intolerable side effects. Through an approach combining high-throughput screening and chemical modification, we developed CN06 as a dual activator of the constitutive androstane receptor (CAR) and nuclear factor erythroid 2-related factor 2 (Nrf2). CN06 enhances CAR-induced bioactivation of CPA (a prodrug) by provoking hepatic expression of CYP2B6, while repressing DOX-induced cytotoxicity in cardiomyocytes in vitro via stimulating Nrf2-antioxidant signaling. Utilizing a multicellular coculture model incorporating human primary hepatocytes, TNBC cells, and cardiomyocytes, we show that CN06 increased CPA/DOX-mediated TNBC cell death via CAR-dependent CYP2B6 induction and subsequent conversion of CPA to its active metabolite 4-hydroxy-CPA, while protecting against DOX-induced cardiotoxicity by selectively activating Nrf2-antioxidant signaling in cardiomyocytes but not in TNBC cells. Furthermore, CN06 preserves the viability and function of human iPSC–derived cardiomyocytes by modulating antioxidant defenses, decreasing apoptosis, and enhancing the kinetics of contraction and relaxation. Collectively, our findings identify CAR and Nrf2 as potentially novel combined therapeutic targets whereby CN06 holds the potential to improve the efficacy/toxicity ratio of CPA/DOX-containing chemotherapy.