Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, 3-020R Katz Group Centre for Pharmacy and Health Research, Edmonton, AB, T6G 2E1, Canada.
Department of Chemistry, Faculty of Science, University of Alberta, Edmonton, Canada.
Sci Rep. 2021 Jun 3;11(1):11757. doi: 10.1038/s41598-021-91344-7.
Invasive breast cancer (BrCa) is predicted to affect 1 in 9 women in a lifetime;1 in 32 will die from this disease. The most aggressive forms of BrCa, basal-like/triple-negative phenotype (TNBC), are challenging to treat and result in higher mortality due high number of metastatic cases. There is a paucity of options for TNBC treatment, which highlights the need for additional innovative treatment approaches. NIH-III mice were injected in the abdominal mammary fat pad with luciferase-expressing derivative of the human TNBC cell line, MDA-MB-231 cells. Animals were gavage-fed with nitrofen at the doses of 1, 3 or 6 mg/kg/alternate days. However, several structural properties/components of nitrofen raise concerns, including its high lipophilicity (cLogP of nearly 5) and a potential toxophore in the form of a nitroarene group. Therefore, we developed analogues of nitrofen which lack the nitro group and/or have replaced the diaryl ether linker with a diarylamine that could allow modulation of polarity. In vitro anti-invasiveness activity of nitrofen analogues were evaluated by quantitative determination of invasion of MDA-MB-231-Luciferase cells through Matrigel using a Boyden chamber. Our in vivo data show that nitrofen efficiently blocks TNBC tumor metastasis. In vitro data suggest that this is not due to cytotoxicity, but rather is due to impairment of invasive capacity of the cells. Further, using an in vitro model of EMT, we show that nitrofen interferes with the process of EMT and promotes mesenchymal to epithelial transformation. In addition, we show that three of the nitrofen analogues significantly reduced invasive potential of TNBC cells, which may, at least partially, be attributed to the analogues' ability to promote mesenchymal to epithelial-like transformation of TNBC cells. Our study shows that nitrofen, and more importantly its analogues, are significantly effective in limiting the invasive potential of TNBC cell lines with minimal cytotoxic effect. Further, we demonstrate that nitrofen its analogues, are very effective in reversing mesenchymal phenotype to a more epithelial-like phenotype. This may be significant for the treatment of patients with mesenchymal-TNBC tumor subtype who are well known to exhibit high resistance to chemotherapy.
浸润性乳腺癌（BrCa）预计会影响女性一生中的 1/9；其中 1/32 将死于这种疾病。最具侵袭性的乳腺癌，基底样/三阴性表型（TNBC），治疗具有挑战性，并且由于大量转移病例导致死亡率较高。TNBC 治疗选择有限，这凸显了需要额外的创新治疗方法。NIH-III 小鼠在腹部乳腺脂肪垫中注射了表达荧光素酶的人类 TNBC 细胞系 MDA-MB-231 细胞的衍生物。动物通过灌胃给予硝基芬，剂量为 1、3 或 6mg/kg/隔日。然而，硝基芬的几个结构特性/组成部分引起了关注，包括其高亲脂性（几乎为 5 的 cLogP）和硝基芳烃基团的潜在毒代基团。因此，我们开发了缺乏硝基基团的硝基芬类似物，或者用二芳基胺取代二芳基醚键，这可能允许调节极性。通过使用 Boyden 室定量测定 MDA-MB-231-Luciferase 细胞穿过 Matrigel 的侵袭性，评估了硝基芬类似物的体外抗侵袭活性。我们的体内数据表明，硝基芬有效地阻止了 TNBC 肿瘤转移。体外数据表明，这不是由于细胞毒性，而是由于细胞侵袭能力受损。此外，使用 EMT 的体外模型，我们表明硝基芬干扰 EMT 过程并促进间质到上皮的转化。此外，我们表明，三种硝基芬类似物显著降低了 TNBC 细胞的侵袭潜力，这至少部分归因于类似物促进 TNBC 细胞间质到上皮样转化的能力。我们的研究表明，硝基芬及其类似物在限制 TNBC 细胞系的侵袭潜力方面非常有效，而对细胞的细胞毒性作用最小。此外，我们证明硝基芬及其类似物非常有效地将间充质表型逆转为更上皮样表型。对于治疗众所周知对化疗具有高抗性的间质-TNBC 肿瘤亚型的患者，这可能具有重要意义。
