Sólimo A M, Soraires Santacruz M C, Vanzulli S, Coggiola O, Bal de Kier Joffé E, Finkielsztein L, Callero M A
Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo", Área Investigación, Dpto. Inmunobiología, Ciudad Autónoma de Buenos Aires, Argentina.
Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Argentina.
Heliyon. 2020 Oct 6;6(10):e05161. doi: 10.1016/j.heliyon.2020.e05161. eCollection 2020 Oct.
Advanced triple negative breast cancer (ATNBC) is defined by a lack of expression of hormones receptors as well as HER2/neu and its high probability of visceral metastasis. This pathology is associated with a poor prognosis. Previously, we found that T2, an -arylsubstituted thiosemicarbazone ( -TSC), had cytotoxic effect on human breast cancer cells lines. Hence, in this study, we investigated the anti-metastasic action of T2 on ATNBC.
In order to deepen T2 action mode on ATNBC, we first confirmed T2 cytotoxicity on a panel of TNBC cells and then continued studying T2 effects an on the syngeneic 4T1 mouse model.
We found that T2 had a cytotoxic effect comparable to chemotherapeutics used in present treatment schemes for ATNBC. T2 treatment not only induced apoptosis, but it also down-modulated 4T1 invasive and metastatic-associated capacities, such as clonogenicity, migration and metallo-proteases activity. Moreover, this agent reduced the number of 4T1 cancer stem cells. Finally, T2 treatment induced a more differentiated cell phenotype and the overexpression of the metastasis suppressor gene NDRG-1. assays showed that T2 reduced tumor burden, down modulated local tumor invasion and significantly reduced the number of lung metastases in the 4T1 advanced TNBC murine model, while the compound did not exhibit intolerable toxicity.
This study provided evidence that T2 not only exerted an anti-tumor activity but it also showed anti-invasive and anti-metastatic actions on ATNBC and , suggesting that T2 could be considered as a promising therapy that deserves further analysis.
晚期三阴性乳腺癌（ATNBC）的定义是缺乏激素受体以及HER2/neu的表达，并且其内脏转移的可能性很高。这种病理与预后不良相关。此前，我们发现T2，一种芳基取代的硫代半卡巴腙（芳基-TSC），对人乳腺癌细胞系具有细胞毒性作用。因此，在本研究中，我们研究了T2对ATNBC的抗转移作用。
为了深入了解T2对ATNBC的作用模式，我们首先在一组三阴乳腺癌细胞上证实了T2的细胞毒性，然后继续研究T2对同基因4T1小鼠模型的影响。
我们发现T2具有与目前用于治疗ATNBC的化疗药物相当的细胞毒性作用。T2处理不仅诱导细胞凋亡，还下调了4T1的侵袭和转移相关能力，如克隆形成能力、迁移能力和金属蛋白酶活性。此外，该药物减少了4T1癌症干细胞的数量。最后，T2处理诱导了更分化的细胞表型，并使转移抑制基因NDRG-1过表达。实验表明，T2降低了肿瘤负荷，下调了局部肿瘤侵袭，并显著减少了4T1晚期三阴乳腺癌小鼠模型中的肺转移数量，而该化合物未表现出无法耐受的毒性。
本研究提供了证据表明，T2不仅发挥了抗肿瘤活性，还对ATNBC显示出抗侵袭和抗转移作用，表明T2可被视为一种有前途的治疗方法，值得进一步分析。
