Transferrin–cisplatin specifically deliver cisplatin to HepG2 cells in vitro and enhance cisplatin cytotoxicity

Cisplatin is a major broad-spectrum chemotherapeutic agent, however, its dose-dependent side effects limit the administration of large doses. Presently, developing a drug targeted delivery system is suggested as one of the most promising approaches to minimize the side effects of cisplatin. Here, we found that each human serum transferrin (HTf) has the potential to bind with over 22 cisplatins, and the complex of apo-HTf–cisplatin can specifically deliver cisplatin to HepG2 cells (human hepatocellular liver carcinoma cell line) in vitro, and facilitate HepG2 cells to apoptosis. Moreover, proteomics methods revealed that the abundances of 23 proteins in HepG2 cells were remarkably altered in response to cisplatin/apo-HTf–cisplatin exposure, and Realtime-PCR revealed that a number of important genes related to chemotherapeutic cytotoxicity and chemotherapeutic resistance are differentially transcribed between the HepG2 cells of cisplatin exposed and HTf–cisplatin exposed. The pathway analysis of the differentially expressed proteins and gene transcriptions indicated that those regulated proteins and gene transcriptions are involved in apoptosis regulation, transcription, cell cycle control, protein biosynthesis, energy metabolism, signal transduction, protein binding and other functions. It indicated that the cisplatin toxicity in HepG2 cell is diverse, the transport process has an effect on the cisplatin cytotoxicity, and the mechanism of the apoptosis of HepG2 cells induced by apo-HTf–cisplatin is different from that of cisplatin.

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► Binding ability of HTf with cisplatin can be adjusted by pH.
► Complex of apo-HTf–cisplatin can specifically deliver to cancer cell lines (HepG2 and BEL-7420 cells).
► Complex of apo-HTf–cisplatin can induce more HepG2 cells to apoptosis than free cisplatin does.
► The mechanism of HepG2 cell apoptosis by apo-HTf–cisplatin differs from that of cisplatin.