Effect of Dicycloplatin, a Novel Platinum Chemotherapeutical Drug, on Inhibiting Cell Growth and Inducing Cell Apoptosis

Guang-Quan Li,Xing-Ping Wu,Yong-Ju Liang,Li-Wu Fu,Xiao-Qin Zhao,Xing-Gui Chen,Jing-Dun Xie,Wei-Qiang Chen,Guillermo Velasco

doi:10.1371/journal.pone.0048994

Abstract

Dicycloplatin, a new supramolecular platinum-based antitumor drug, has been approved by the State Food and Administration (SFDA) of China. In this study, we investigated the anticancer activity of dicycloplatin in cancer cells and signaling pathways involved in dicycloplatin-induced apoptosis. Dicycloplatin inhibited the proliferation of cancer cells and increased the percentage of apoptosis in a concentration-dependent manner. Besides, some apoptosis related events were observed after treatment with dicycloplatin, including increase of reactive oxygen species (ROS), collapse of mitochondrial membrane potential (Δψm), release of cytochrome c from the mitochondria to the cytosol, upregulation of p53, which were accompanied by activation of caspase-9, caspase-3, caspase-8, and poly (ADP-ribose) polymerase cleavage in a concentration-dependent manner. The role of apoptosis in dicycloplatin-mediated cell death was further confirmed by the concomitant treatment with caspase-8 or caspase-9 inhibitors, which inhibited apoptosis and PARP cleavage. Intracellular glutathione (GSH) was also found to inhibit the cytotoxic effect of dicycloplatin. In conclusion, these findings suggest that dicycloplatin induces apoptosis through ROS stress-mediated death receptor pathway and mitochondrial pathway which is similar to carboplatin.

Highlights

Platinum-based anticancer drugs, such as cisplatin and carboplatin, are the first-line clinical anticancer drugs for the treatment of solid tumors [1], including lung, breast, ovarian and head and neck cancers
Induction of Apoptosis by Dicycloplatin To assess apoptosis induced by dicycloplatin in cancer cells, we detected the exposure of phosphatidylserine on the cell surface, Figure 6
Dicycloplatin, a novel platinum chemotherapeutical drug has been reported to exhibit lower toxicity and better anticancer activity compared with cisplatin and carboplatin [13,14,18]

Summary

Introduction

Platinum-based anticancer drugs, such as cisplatin and carboplatin, are the first-line clinical anticancer drugs for the treatment of solid tumors [1], including lung, breast, ovarian and head and neck cancers. Both cisplatin [2,3,4,5] and carboplatin [6,7,8,9] have been shown to inhibit cancer cells growth and induce apoptosis in cancer cells through death receptor pathway and/or mitochondrial pathway. The mechanism by which dicycloplatin induced apoptosis in cancer cells remained unclear

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