Development of Clioquinol Platinum(IV) Conjugates as Autophagy-Targeted Antimetastatic Agents

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.