Liposomal Artificial Red Blood Cell-Based Carbon Monoxide Donor Is a Potent Renoprotectant against Cisplatin-Induced Acute Kidney Injury.

Kazuaki Taguchi,Moeko Tsutsuura,Kazuaki Matsumoto,Yuki Enoki,Yuki Watabe,Hiromi Sakai,Masaki Otagiri,Kana Hiraoka,Yuto Suzuki

doi:10.3390/pharmaceutics14010057

Kazuaki Taguchi, Moeko Tsutsuura + Show 7 more

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https://doi.org/10.3390/pharmaceutics14010057

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Abstract

Cisplatin (CDDP) is an essential anti-tumor agent for chemotherapeutic regimens against various types of cancer. However, the progression of nephrotoxicity, which is the main adverse effect of CDDP, leads to discontinuation of CDDP chemotherapy. Therefore, development of a renoprotectant against CDDP-induced nephrotoxicity is crucial. Here, the potential of a carbon monoxide (CO)-loaded hemoglobin-vesicle (CO-HbV) as a renoprotectant for CDDP-induced nephrotoxicity was evaluated for its renoprotective effects against CDDP-induced nephrotoxicity, inhibitory effects on the anti-tumor activity of CDDP, and anti-tumor activity. In healthy mice, after pretreatment with either saline, HbV, or CO-HbV prior to CDDP administration, only the CO-HbV pretreatment group ameliorated the progression of CDDP-induced nephrotoxicity by suppressing apoptosis via caspase-3. In experiments using B16-F10 melanoma cells, the half-maximal inhibitory concentration of CDDP decreased with co-incubation with CO-HbV, owing to the anti-tumor activity of CO. CO-HbV pretreatment had no impact on the anti-tumor activity of CDDP in B16-F10 melanoma cell-bearing mice, which was consistent with the results of the cell experiment. Furthermore, CO-HbV pretreatment improved body growth and survival rates. In conclusion, CO-HbV pretreatment is a potent renoprotectant for CDDP-induced nephrotoxicity, allowing treatment with CDDP to be conducted without failure of cancer treatment.

Highlights

Cisplatin (CDDP) is the first platinum anti-tumor agent approved by the Food andDrug Administration
Severe damage to tubular but not glomeruli were observed in the kidneys of saline-treated CDDP mice when compared to control mice (Figure 2A,B)
The clinical manifestations of CDDP-induced nephrotoxicity were significantly suppressed by pretreatment with carbon monoxide (CO)-HbV (Figures 1 and 2D) indicating that CO-HbV is a potent renoprotectant against CDDP-induced nephrotoxicity, consistent with the previous findings surrounding CORM-3 [13]

Summary

Introduction

Cisplatin (CDDP) is the first platinum anti-tumor agent approved by the Food andDrug Administration. CDDP treatment develop severe nephrotoxicity [1,2]. According to the European and Japanese guidelines for the prevention of CDDP-induced nephrotoxicity, CDDP hydration by saline before, during, and after CDDP infusion is strongly recommended as a standard pharmaceutical intervention [3,4]. Despite these practices, cancer patients receiving CDDP treatment still suffer from nephrotoxicity [5]. Researchers are gaining interest in identifying renoprotectants to prevent CDDP-induced nephrotoxicity [6,7,8]. Researchers are gaining interest in identifying renoprotectants to prevent CDDP-induced nephrotoxicity [6,7,8]. 4.0/).

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