Chattopadhyay Mitali, Nath Niharika, Kodela Ravinder, Metkar Shalaka, Soyemi Sarin A, Kashfi Khosrow
Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, New York.
Department of Biological and Chemical Sciences, New York Institute of Technology, New York, New York.
J Pharmacol Exp Ther. 2025 Jan;392(1):100019. doi: 10.1124/jpet.124.002240. Epub 2024 Nov 22.
Estrogen receptor (ER)-negative breast cancers are known to be aggressive and unresponsive to antiestrogen therapy, and triple-negative breast cancers are associated with poor prognosis and metastasis. Thus, new targeted therapies are needed. Forkhead box M1 (FOXM1) is abundantly expressed in human cancers and implicated in protecting tumor cells from oxidative stress by reducing the levels of intracellular reactive oxygen species (ROS). Aspirin, a prototypical anticancer agent with deleterious side effects that has been modified to release nitric oxide and hydrogen sulfide is called nitric oxide-hydrogen sulfide-releasing aspirin (NOSH-aspirin, NOSH-ASA), generating a "safer" class of new anti-inflammatory agents. We evaluated NOSH-ASA against ER-negative breast cancer using cell lines and a xenograft mouse model. NOSH-ASA strongly inhibited growth of MDA-MB-231 and SKBR3 breast cancer cells with low ICs of 90 ± 5 and 82 ± 5 nM, respectively, with marginal effects on a normal breast epithelial cell line. NOSH-ASA inhibited cell proliferation, caused G/G phase arrest, increased apoptosis, and was associated with increases in ROS. In MDA-MB-231 cell xenografts, NOSH-ASA reduced tumor size markedly, which was associated with reduced proliferation (decreased proliferating cell nuclear antigen expression), induction of apoptosis (increased terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells), and increased ROS, whereas nuclear factor κ-light-chain-enhancer of activated B cells and FoxM1 that were high in untreated xenografts were significantly reduced. mRNA data for FoxM1, p21, and cyclin D1 corroborated with the respective protein expressions and arrest of cells. Taken together, these molecular events contribute to NOSH-ASA-mediated growth inhibition and apoptotic death of ER-negative breast cells in vitro and in vivo. Additionally, as a ROS inducer and FOXM1 inhibitor, NOSH-ASA has potential as a targeted therapy. SIGNIFICANCE STATEMENT: We examined the cellular effects and xenograft tumor inhibitory potential of NOSH-aspirin, a nitric oxide- and hydrogen sulfide-donating hybrid, against estrogen receptor-negative breast cancer, which currently lacks effective therapeutic options. Inducing reactive oxygen species and downregulating forkhead box M1 are plausible mechanisms contributing to decreased cell proliferation and increased apoptosis. NOSH-aspirin reduced tumor size by 90% without inducing any observable gross toxicity, underscoring its promising translational potential.
雌激素受体（ER）阴性乳腺癌具有侵袭性，且对抗雌激素治疗无反应，三阴性乳腺癌则与预后不良和转移相关。因此，需要新的靶向治疗方法。叉头框M1（FOXM1）在人类癌症中大量表达，并通过降低细胞内活性氧（ROS）水平来保护肿瘤细胞免受氧化应激。阿司匹林是一种具有有害副作用的典型抗癌药物，已被修饰以释放一氧化氮和硫化氢，称为一氧化氮-硫化氢释放阿司匹林（NOSH-阿司匹林，NOSH-ASA），产生了一类“更安全”的新型抗炎药。我们使用细胞系和异种移植小鼠模型评估了NOSH-ASA对ER阴性乳腺癌的作用。NOSH-ASA强烈抑制MDA-MB-231和SKBR3乳腺癌细胞的生长，其IC50分别低至90±5和82±5 nM，对正常乳腺上皮细胞系的影响很小。NOSH-ASA抑制细胞增殖，导致G2/M期阻滞，增加细胞凋亡，并与ROS增加有关。在MDA-MB-231细胞异种移植中，NOSH-ASA显著减小肿瘤大小，这与增殖减少（增殖细胞核抗原表达降低）、凋亡诱导（末端脱氧核苷酸转移酶dUTP缺口末端标记阳性细胞增加）和ROS增加有关，而在未治疗的异种移植中高表达的核因子κB轻链增强子和FoxM1则显著降低。FoxM1、p21和细胞周期蛋白D1的mRNA数据与各自的蛋白质表达及细胞阻滞情况相符。综上所述，这些分子事件促成了NOSH-ASA在体外和体内对ER阴性乳腺细胞的生长抑制和凋亡死亡。此外，作为一种ROS诱导剂和FOXM1抑制剂，NOSH-ASA具有作为靶向治疗的潜力。意义声明：我们研究了一氧化氮和硫化氢供体杂种NOSH-阿司匹林对雌激素受体阴性乳腺癌的细胞效应和异种移植肿瘤抑制潜力，目前该类型乳腺癌缺乏有效的治疗选择。诱导活性氧和下调叉头框M1是导致细胞增殖减少和细胞凋亡增加的合理机制。NOSH-阿司匹林使肿瘤大小减小了90%，且未诱导任何可观察到的明显毒性，突显了其有前景的转化潜力。
