Abstract

Breast cancer (BC) and endocrine resistance to chemotherapy are challenging problems where angiogenesis plays fundamental roles. Thus, targeting of VEGFR-2 signalling pathway has been an attractive approach. In this study, we synthesised a new sorafenib analogue, thieno[2,3-d]pyrimidine based urea derivative, KM6. It showed 65% inhibition of VEGF2 tyrosine kinase activity and demonstrated a potential antitumor activity in TAM-resistant, LCC2, and its parental MCF7 BC cells. KM6 retained the sensitivity of LCC2 through upregulation of key enzymes of apoptosis and proteins of cell death including caspases 3, 8, 9, P53, BAX/BCL-2 ratio and LDH in media. It downregulated mRNA expression of Ki-67, survivin, Akt, and reduced levels of ROS and glucose uptake. Moreover, KM6 reduced the levels of inflammation markers PGE2, COX2, IL-1β and IL6 and metastasis markers MMP-2 and MMP-9. In conclusion, KM6 is a promising compound for ER + and TAM-resistant BC with many potential antitumor and polypharmacological mechanisms.

摘要

乳腺癌（BC）和内分泌对化疗的耐药性是具有挑战性的问题，其中血管生成起着基本作用。因此，靶向VEGFR-2信号传导途径已经是有吸引力的方法。在这项研究中，我们合成了一种新的索拉非尼类似物，基于噻吩并[2,3- d ]嘧啶的脲衍生物KM6。它显示出对VEGF2酪氨酸激酶活性的65％抑制作用，并在耐TAM的LCC2及其亲代MCF7 BC细胞中显示出潜在的抗肿瘤活性。KM6通过上调细胞凋亡的关键酶和细胞死亡蛋白（包括半胱氨酸蛋白酶3、8、9，P53，BAX / BCL-2比例和培养基中的LDH）来保持LCC2的敏感性。它下调Ki-67，survivin，Akt的mRNA表达，并降低ROS和葡萄糖摄取水平。此外，KM6降低了炎症标志物PGE2，COX2，IL-1β和IL6以及转移标志物MMP-2和MMP-9的水平。总之，KM6是具有ERP和TAM耐药性的BC的有前途的化合物，具有许多潜在的抗肿瘤和多药理学机制。