Ketoplatin in Triple-negative Breast Cancer Cells MDA-MB-231: High Efficacy and Low Toxicity, and Positive Impact on Inflammatory Microenvironment

Triple-negative breast cancer (TNBC) shares the molecular features facilitating epithelial-to-mesenchymal transition (EMT), which contributed to tumor invasion and metastasis. A platinum(IV) conjugate ketoplatin deriving from FDA-approved drugs cisplatin and ketoprofen was designed and prepared to enhance antitumor activity and suppress EMT in TNBC via positive impact on inflammatory microenvironment by modulating COX-2 signal. As a prodrug, ketoplatin afforded 50.26-fold higher cytotoxicity than cisplatin against TNBC mesenchymal-stem cell-like MDA-MB-231 cells, partly attributing to its dramatic increase of cellular uptake and DNA damage. More importantly, EMT progress in MDA-MB-231 was markedly restrained by ketoplatin, resulting from the suppression of vimentin and N-cadherin mediated by down-regulated COX-2. Further in vivo investigation exhibited that ketoplatin effectively inhibited tumor growth and reduced systemic toxicity compared to cisplatin. Overall, ketoplatin possessed high antitumor activity and low toxicity against TNBC MDA-MB-231 in vitro and in vivo.