Brandolini Laura, Cristiano Loredana, Fidoamore Alessia, De Pizzol Maria, Di Giacomo Erica, Florio Tiziana Marilena, Confalone Giuseppina, Galante Angelo, Cinque Benedetta, Benedetti Elisabetta, Ruffini Pier Adelchi, Cifone Maria Grazia, Giordano Antonio, Alecci Marcello, Allegretti Marcello, Cimini Annamaria
Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, Italy.
Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
Oncotarget. 2015 Dec 22;6(41):43375-94. doi: 10.18632/oncotarget.6234.
In breast cancer it has been proposed that the presence of cancer stem cells may drive tumor initiation, progression and recurrences. IL-8, up-regulated in breast cancer, and associated with poor prognosis, increases CSC self-renewal in cell line models. It signals via two cell surface receptors, CXCR1 and CXCR2. Recently, the IL-8/CXCR1 axis was proposed as an attractive pathway for the design of specific therapies against breast cancer stem cells. Reparixin, a powerful CXCR1 inhibitor, was effective in reducing in vivo the tumour-initiating population in several NOD/SCID mice breast cancer models, showing that the selective targeting of CXCR1 and the combination of reparixin and docetaxel resulted in a concomitant reduction of the bulk tumour mass and CSC population. The available data indicate that IL-8, expressed by tumour cells and induced by chemotherapeutic treatment, is a key regulator of the survival and self-renewal of the population of CXCR1-expressing CSC. Consequently, this investigation on the mechanism of action of the reparixin/paclitaxel combination, was based on the observation that reparixin treatment contained the formation of metastases in several experimental models. However, specific data on the formation of breast cancer brain metastases, which carry remarkable morbidity and mortality to a substantial proportion of advanced breast cancer patients, have not been generated. The obtained data indicate a beneficial use of the drug combination reparixin and paclitaxel to counteract brain tumour metastasis due to CSC, probably due to the combined effects of the two drugs, the pro-apoptotic action of paclitaxel and the cytostatic and anti-migratory effects of reparixin.
在乳腺癌中，有人提出癌症干细胞的存在可能驱动肿瘤的起始、进展和复发。白细胞介素-8（IL-8）在乳腺癌中上调，且与预后不良相关，在细胞系模型中可增加癌症干细胞的自我更新。它通过两种细胞表面受体CXCR1和CXCR2发出信号。最近，IL-8/CXCR1轴被认为是设计针对乳腺癌干细胞的特异性疗法的一个有吸引力的途径。瑞帕霉素是一种强效的CXCR1抑制剂，在多个NOD/SCID小鼠乳腺癌模型中，它能有效减少体内肿瘤起始细胞群，表明选择性靶向CXCR1以及瑞帕霉素与多西他赛联合使用可使实体瘤块和癌症干细胞群同时减少。现有数据表明，由肿瘤细胞表达并经化疗诱导产生的IL-8是表达CXCR1的癌症干细胞群存活和自我更新的关键调节因子。因此，这项关于瑞帕霉素/紫杉醇联合作用机制的研究基于这样的观察结果：在多个实验模型中，瑞帕霉素治疗可抑制转移的形成。然而，尚未产生关于乳腺癌脑转移形成的具体数据，而脑转移对相当一部分晚期乳腺癌患者具有显著的发病率和死亡率。所获得的数据表明，瑞帕霉素和紫杉醇联合用药可有效对抗由癌症干细胞导致的脑肿瘤转移，这可能是由于两种药物的联合作用、紫杉醇的促凋亡作用以及瑞帕霉素的细胞抑制和抗迁移作用。
