Bhattacharya Udayan, Kamran Mohammad, Manai Maroua, Cristofanilli Massimo, Ince Tan A
Weill Cornell Medicine, Department of Pathology and Laboratory Medicine, New York, NY 10065, USA.
Weill Cornell Medicine, Division of Hematology-Oncology, New York, NY 10065, USA.
Cancers (Basel). 2023 Jan 4;15(2):332. doi: 10.3390/cancers15020332.
We recently identified a cell-of-origin-specific mRNA signature associated with metastasis and poor outcome in triple-negative carcinoma (TNBC). This TNBC cell-of-origin signature is associated with the over-expression of histone deacetylases and zinc finger protein HDAC1, HDAC7, and ZNF92, respectively. Based on this signature, we discovered that the combination of three drugs (an HDAC inhibitor, an anti-helminthic Niclosamide, and an antibiotic Tanespimycin that inhibits HSP90) synergistically reduces the proliferation of the twelve tested TNBC cell lines. Additionally, we discovered that four out of five inflammatory breast carcinoma cell lines are sensitive to this combination. Significantly, the concentration of the drugs that are used in these experiments are within or below clinically achievable dose, and the synergistic activity only emerged when all three drugs were combined. Our results suggest that HDAC and HSP90 inhibitors combined with the tapeworm drug Niclosamide can achieve remarkably synergistic inhibition of TNBC and IBC. Since Niclosamide, HDAC, and HSP90 inhibitors were approved for clinical use for other cancer types, it may be possible to repurpose their combination for TNBC and IBC.
我们最近鉴定出一种起源细胞特异性的mRNA特征，其与三阴性乳腺癌（TNBC）的转移及不良预后相关。这种TNBC起源细胞特征分别与组蛋白去乙酰化酶以及锌指蛋白HDAC1、HDAC7和ZNF92的过表达有关。基于这一特征，我们发现三种药物（一种HDAC抑制剂、一种抗蠕虫药氯硝柳胺以及一种抑制HSP90的抗生素坦螺旋霉素）联合使用可协同降低所检测的12种TNBC细胞系的增殖。此外，我们发现5种炎性乳腺癌细胞系中有4种对这种联合用药敏感。值得注意的是，这些实验中所使用的药物浓度在临床可达到的剂量范围内或以下，并且只有当三种药物联合使用时才会出现协同活性。我们的结果表明，HDAC和HSP90抑制剂与绦虫药氯硝柳胺联合使用可对TNBC和炎性乳腺癌（IBC）实现显著的协同抑制作用。由于氯硝柳胺、HDAC和HSP90抑制剂已被批准用于其他癌症类型的临床治疗，因此有可能将它们的联合用药用于TNBC和IBC的治疗。
