Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, India.
Life Sci. 2020 Sep 1;256:117976. doi: 10.1016/j.lfs.2020.117976. Epub 2020 Jun 16.
We have previously reported that Centchroman (CC), an oral contraceptive drug, inhibits breast cancer progression and metastasis. In this study, we investigated whether CC inhibits local invasion of tumor cells and/or their metastatic colonization with detailed underlying mechanisms.
The effect of CC on the experimental metastasis and spontaneous metastasis was demonstrated by using tail-vein and orthotopic 4T1-syngeneic mouse tumor models, respectively. The anti-angiogenic potential of CC was evaluated using well established in vitro and in vivo models. The role of RAC1/PAK1/β-catenin signaling axis in the metastasis was investigated and validated using siRNA-mediated knockdown of PAK1 as well as by pharmacological PAK1-inhibitor.
The oral administration of CC significantly suppressed the formation of metastatic lung nodules in the 4T1-syngeneic orthotopic as well as experimental metastatic models. More importantly, CC treatment suppressed the tube formation and migration capacities of human umbilical vein endothelial cells (HUVEC) and inhibited pre-existing vasculature as well as the formation of neovasculature. The suppression of migration and invasion capacities of metastatic breast cancer cells upon CC treatment was associated with the inhibition of small GTPases (Rac1 and Cdc42) concomitant with the downregulation of PAK1 and downstream β-catenin signaling. In addition, CC upregulated the expression of miR-145, which is known to target PAK1.
This study warrants the repurposing of CC as a potential therapeutic agent against metastatic breast cancer.
我们之前曾报道过，口服避孕药 Centchroman（CC）能够抑制乳腺癌的进展和转移。在这项研究中，我们研究了 CC 是否通过潜在的机制抑制肿瘤细胞的局部浸润及其转移性定植。
分别通过尾静脉和原位 4T1 同源小鼠肿瘤模型，证明 CC 对实验性转移和自发性转移的作用。使用已建立的体外和体内模型评估 CC 的抗血管生成潜力。使用 siRNA 介导的 PAK1 敲低以及药理学 PAK1 抑制剂，研究并验证 RAC1/PAK1/β-catenin 信号轴在转移中的作用。
CC 的口服给药显著抑制了 4T1 同源原位和实验性转移模型中转移性肺结节的形成。更重要的是，CC 治疗抑制了人脐静脉内皮细胞（HUVEC）的管形成和迁移能力，并抑制了预先存在的血管和新血管的形成。CC 处理抑制转移性乳腺癌细胞的迁移和侵袭能力与小 GTPases（Rac1 和 Cdc42）的抑制同时伴随着 PAK1 和下游 β-catenin 信号的下调有关。此外，CC 上调了 miR-145 的表达，已知其可靶向 PAK1。
这项研究证明了将 CC 重新用作治疗转移性乳腺癌的潜在治疗剂是合理的。
