RESUMEN
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.
Asunto(s)
Antineoplásicos/administración & dosificación , Cisplatino/análogos & derivados , Cetoprofeno/administración & dosificación , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Microambiente Tumoral/efectos de los fármacos , Células A549 , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Antineoplásicos/química , Cisplatino/administración & dosificación , Cisplatino/química , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/fisiología , Femenino , Células HeLa , Humanos , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Cetoprofeno/análogos & derivados , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
The great interest in epithelial-to-mesenchymal transition (EMT) programme lies in its association with process of metastasis and invasion, which is a crucial cause of cancer-related death. Herein, we designed and reported three new NSAID-Pt(IV) prodrugs, taking Non-Steroid Anti-Inflammatory Drugs (NSAIDs) to disrupt EMT programme and assist genotoxic platinum-based drugs as a cytotoxicity booster, to offer a class of potential anticarcinogens with a multi-functional action mechanism. The NSAID-Pt(IV) prodrugs, especially Eto-Pt(IV), highly enhanced cellular uptake with amount up to 42-fold at 3â¯h compared with CDDP, and greatly increased DNA damage and cell apoptosis, showing much higher cytotoxicity than cisplatin in the tested cancer cells even in A549/cis cells. Among of them, Eto-Pt(IV) and Car-Pt(IV) exhibited more excellent activity than Sul-Pt(IV), arising from their reduction-labile and favorable lipophilicity. Most strikingly, Eto-Pt(IV) markedly inhibited metastasis and invasion of MCF-7â¯cells, owing to its COX-2 suppression that down-regulated active MMP-2, vimentin protein and up-regulated E-cadherin. In vivo, Eto-Pt(IV) displayed potent antitumor activity and no observable toxicity in BALB/c nude mice bearing MCF-7 tumors.