化学
自噬
PI3K/AKT/mTOR通路
癌症研究
细胞生物学
血管生成
蛋白激酶B
顺铂
体内
DNA损伤
生物化学
DNA
生物
细胞凋亡
遗传学
生物技术
化疗
作者
Ming Zhang,Linming Li,Suying Li,Zhifang Liu,Ning Zhang,Bin Sun,Zhengping Wang,Dianlong Jia,Min Liu,Qingpeng Wang
标识
DOI:10.1021/acs.jmedchem.2c01895
摘要
A series of autophagy-targeted antimetastatic clioquinol (CLQ) platinum(IV) conjugates were designed and prepared by incorporating an autophagy activator CLQ into the platinum(IV) system. Complex 5 with the cisplatin core bearing dual CLQ ligands with potent antitumor properties was screened out as a candidate. More importantly, it displayed potent antimetastatic properties both in vitro and in vivo as expected. Mechanism investigation manifested that complex 5 induced serious DNA damage to increase γ-H2AX and P53 expression and caused mitochondria-mediated apoptosis through the Bcl-2/Bax/caspase3 pathway. Then, it promoted prodeath autophagy by suppressing PI3K/AKT/mTOR signaling and activating the HIF-1α/Beclin1 pathway. The T-cell immunity was elevated by restraining the PD-L1 expression and subsequently increasing CD3+ and CD8+ T cells. Ultimately, metastasis of tumor cells was suppressed by the synergistic effects of DNA damage, autophagy promotion, and immune activation aroused by CLQ platinum(IV) complexes. Key proteins VEGFA, MMP-9, and CD34 tightly associated with angiogenesis and metastasis were downregulated.
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