Nayeem Nazia, Sauma Sami, Ahad Afruja, Rameau Rachele, Kebadze Sophia, Bazett Mark, Park Brian J, Casaccia Patrizia, Prabha Swayam, Hubbard Karen, Contel Maria
Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York 11210, United States.
Brooklyn College Cancer Center, Brooklyn College, The City University of New York, Brooklyn, New York 11210, United States.
ACS Pharmacol Transl Sci. 2024 Apr 5;7(5):1364-1376. doi: 10.1021/acsptsci.4c00020. eCollection 2024 May 10.
Triple negative breast cancer (TNBC) represents a subtype of breast cancer that does not express the three major prognostic receptors of human epidermal growth factor receptor 2 (HER2), progesterone (PR), and estrogen (ER). This limits treatment options and results in a high rate of mortality. We have reported previously on the efficacy of a water-soluble, cationic organometallic compound () in a TNBC mouse xenograft model with impressive tumor reduction and targeted tumor drug accumulation. inhibits cancer hallmarks such as migration, angiogenesis, and invasion in TNBC cells by a mechanism that generates apoptotic cell death. displays little interaction with DNA and appears to act by a P53-independent pathway. We report here on the mitochondrial alterations caused by treatment and detail the inhibitory properties of in the PI3K/AKT/mTOR pathway in MDA-MB-231 cells. Lastly, we describe the results of an efficacy study of the TNBC xenografted mouse model with and Olaparib monotherapy and combinatory treatments. We find 59% tumor shrinkage with and 65% with the combination. Histopathological analysis confirmed no test-article-related toxicity. Immunohistochemical analysis indicated an inhibition of the angiogenic marker CD31 and increased levels of apoptotic cleaved caspase 3 marker, along with a slight inhibition of p-mTOR. Taken together, the effects of in vitro show similar trends and translation in vivo Our investigation underscores the therapeutic potential of in addressing the challenges posed by TNBC as evidenced by its robust efficacy in inhibiting key cancer hallmarks, substantial tumor reduction, and minimal systemic toxicity.
三阴性乳腺癌（TNBC）是乳腺癌的一种亚型，不表达人类表皮生长因子受体2（HER2）、孕激素（PR）和雌激素（ER）这三种主要的预后受体。这限制了治疗选择，导致高死亡率。我们之前报道了一种水溶性阳离子有机金属化合物（）在TNBC小鼠异种移植模型中的疗效，该化合物能显著减少肿瘤并实现靶向肿瘤药物积累。 通过产生凋亡性细胞死亡的机制抑制TNBC细胞中的迁移、血管生成和侵袭等癌症特征。 与DNA的相互作用很小，似乎通过一条不依赖P53的途径发挥作用。我们在此报告 治疗引起的线粒体改变，并详细阐述 对MDA-MB-231细胞中PI3K/AKT/mTOR途径的抑制特性。最后，我们描述了 在TNBC异种移植小鼠模型中与奥拉帕尼单药治疗及联合治疗的疗效研究结果。我们发现 单药治疗使肿瘤缩小59%，联合治疗使肿瘤缩小65%。组织病理学分析证实无与受试物相关的毒性。免疫组织化学分析表明血管生成标志物CD31受到抑制，凋亡裂解型半胱天冬酶3标志物水平升高，同时p-mTOR受到轻微抑制。综上所述， 在体外的作用显示出与体内相似的趋势和转化。我们的研究强调了 在应对TNBC所带来挑战方面的治疗潜力，这体现在其在抑制关键癌症特征、显著减少肿瘤和最小化全身毒性方面的强大疗效。
