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Updated: Jul 28, 2025
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
A cisplatin conjugate with tumor cell specificity exhibits antitumor effects in renal cancer models
Stefan Mrdenovic1,2,3, Yanping Wang4, Lijuan Yin2
1Division of Hematology, Department of Internal Medicine, University Hospital Osijek, Osijek, Croatia.
Background:
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and is notorious for its resistance to both chemotherapy and small-molecule inhibitor targeted therapies. Subcellular targeted cancer therapy may thwart the resistance to produce a substantial effect.
Methods:
We tested whether the resistance can be circumvented by subcellular targeted cancer therapy with DZ-CIS, which is a chemical conjugate of the tumor-cell specific heptamethine carbocyanine dye (HMCD) with cisplatin (CIS), a chemotherapeutic drug with limited use in ccRCC treatment because of frequent renal toxicity.
Results:
DZ-CIS displayed cytocidal effects on Caki-1, 786-O, ACHN, and SN12C human ccRCC cell lines and mouse Renca cells in a dose-dependent manner and inhibited ACHN and Renca tumor formation in experimental mouse models. Noticeably, in tumor-bearing mice, repeated DZ-CIS use did not cause renal toxicity, in contrast to the CIS-treated control animals. In ccRCC tumors, DZ-CIS treatment inhibited proliferation markers but induced cell death marker levels. In addition, DZ-CIS at half maximal inhibitory concentration (IC50) sensitized Caki-1 cells to small-molecule mTOR inhibitors. Mechanistically, DZ-CIS selectively accumulated in ccRCC cells' subcellular organelles, where it damages the structure and function of mitochondria, leading to cytochrome C release, caspase activation, and apoptotic cancer cell death.
Conclusions:
Results from this study strongly suggest DZ-CIS be tested as a safe and effective subcellular targeted cancer therapy.
Insights
Subcellular targeted cancer therapy with DZ-CIS shows promise for treating clear cell renal cell carcinoma (ccRCC). This novel approach circumvents drug resistance and reduces toxicity, offering a potentially safer and more effective treatment option for kidney cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Clear cell renal cell carcinoma (ccRCC) exhibits significant resistance to conventional chemotherapy and targeted therapies.
- Subcellularly targeted cancer treatments offer a potential strategy to overcome this resistance.
Purpose of the Study:
- To evaluate the efficacy and safety of DZ-CIS, a novel subcellularly targeted therapy, in treating ccRCC.
- To investigate whether DZ-CIS can circumvent existing resistance mechanisms in ccRCC.
Main Methods:
- DZ-CIS, a conjugate of heptamethine carbocyanine dye (HMCD) and cisplatin (CIS), was tested against human ccRCC cell lines (Caki-1, 786-O, ACHN, SN12C) and mouse Renca cells.
- In vivo studies involved experimental mouse models to assess tumor formation inhibition and renal toxicity.
- Mechanistic studies examined DZ-CIS accumulation, mitochondrial damage, and induction of apoptosis.
Main Results:
- DZ-CIS demonstrated dose-dependent cytocidal effects on ccRCC cell lines and inhibited tumor formation in vivo.
- Unlike cisplatin alone, DZ-CIS did not induce renal toxicity in tumor-bearing mice.
- DZ-CIS induced apoptosis in ccRCC cells by damaging mitochondria and sensitizing cells to mTOR inhibitors.
Conclusions:
- DZ-CIS exhibits potent anti-cancer activity against ccRCC.
- DZ-CIS represents a safe and effective subcellularly targeted therapeutic strategy for ccRCC.
- Further clinical investigation of DZ-CIS for ccRCC treatment is warranted.
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