PDF(Pubmed)
Abstract：
Monopolar spindle 1 kinase (Mps1, also known as TTK protein kinase) inhibitors exert marked anticancer effects against triple‑negative breast cancer (TNBC) by causing genomic instability and cell death. As aneuploid cells are vulnerable to compounds that induce energy stress through adenosine monophosphate‑activated protein kinase (AMPK) activation, the synergistic effect of Mps1/TTK inhibition and AMPK activation was investigated in the present study. The combined effects of CFI‑402257, an Mps1/TTK inhibitor, and AICAR, an AMPK agonist, were evaluated in terms of cytotoxicity, cell‑cycle distribution, and in vivo xenograft models. Additional molecular mechanistic studies were conducted to elucidate the mechanisms underlying apoptosis and autophagic cell death. The combination of CFI‑402257 and AICAR showed selective cytotoxicity in a TNBC cell line. The formation of polyploid cells was attenuated, and apoptosis was increased by the combination treatment, which also induced autophagy through dual inhibition of the PI3K/Akt/mTOR and mitogen‑activated protein kinase (MAPK) signaling pathways. Additionally, the combination therapy showed strongly improved efficacy in comparison with CFI‑402257 and AICAR monotherapy in the MDA‑MB‑231 xenograft model. The present study suggested that the combination of CFI‑402257 and AICAR is a promising therapeutic strategy for TNBC.
摘要：
单极纺锤体1激酶（Mps1，也称为TTK蛋白激酶）抑制剂通过引起基因组不稳定和细胞死亡，对三阴性乳腺癌（TNBC）发挥明显的抗癌作用。由于非整倍体细胞容易受到通过腺苷一磷酸活化蛋白激酶（AMPK）活化诱导能量应激的化合物的影响，本研究研究了Mps1/TTK抑制和AMPK激活的协同作用。Mps1/TTK抑制剂CFI‑402257的联合作用，AICAR,AMPK激动剂,根据细胞毒性进行评估，细胞周期分布，和体内异种移植模型。进行了其他分子机制研究以阐明凋亡和自噬性细胞死亡的潜在机制。CFI‑402257和AICAR的组合在TNBC细胞系中显示选择性细胞毒性。多倍体细胞的形成减弱，联合治疗增加了细胞凋亡，它还通过对PI3K/Akt/mTOR和丝裂原激活的蛋白激酶（MAPK）信号通路的双重抑制来诱导自噬。此外,在MDA‑MB‑231异种移植模型中,与CFI‑402257和AICAR单药治疗相比,联合治疗显示出显著改善的疗效.本研究表明，CFI-402257和AICAR的联合治疗是一种有前途的TNBC治疗策略。
