Novel captopril-valproic acid platinum(IV) hybrids with potent antiproliferative and antimetastatic activities targeting fibrosis and DNA-repair

Novel three-component platinum(IV) hybrids were developed as antitumor agents. • The conjugates were potent in inhibiting tumor proliferation and metastasis. • Activate by inhibiting fibrosis and DNA repair, and reversing multidrug resistance. • Potent in inhibiting inflammation and EMT, and boosting antitumor immunity. Fibrosis and DNA repair are crucial factors for cancer development and metastasis. Here, three-component platinum(IV) hybrids with captopril (CTP) and valproic acid (VPA) functional ligands were developed as antiproliferative and antimetastatic agents. These agents exerted effects by inducing DNA damage, suppressing fibrosis and inhibiting DNA repair. Upon activation, the platinum core bound to DNA and caused mitochondria-mediated apoptosis through the Bcl-2/Bax/caspase-3 pathway. The VPA moiety inhibited the key enzyme HDAC3, disrupted DNA-repair by modulating the proteins P-gp, PARP, and PTEN, and further overcame multidrug resistance (MDR). Furthermore, the TGF-β1/Smad2 and MMPs cascades were inhibited by CTP, while tumor inflammation was also inhibited through downregulating COX-2, TNF-α, and IL-6. These combined actions displayed a synergistic role in attenuating tumor fibrosis, and further reversed EMT. In addition, decreased PD-L1 expression and increased infiltration of CD3 + and CD8 + T cells were observed, leading to the initiation of antitumor immunity in tumors. Download: Download high-res image (308KB) Download: Download full-size image