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

Abstract

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 <b>5</b> 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 <i>in vitro</i> and <i>in vivo</i> as expected. Mechanism investigation manifested that complex <b>5</b> induced serious DNA damage to increase <i>γ-</i>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.