Abstract
Cisplatin is a widely used drug in the treatment of various solid tumors, such as ovarian cancer. However, while the acquired resistance significantly limits the success of therapy, some tumors, such as colorectal cancer, are intrinsically insensitive to cisplatin. Only a small amount of intracellular platinum binds to the target—genomic DNA. The fate of the remaining drug is largely obscure. This work aimed to identify the cytosolic protein binding partners of cisplatin in ovarian and colorectal cancer cells and to evaluate their relevance for cell sensitivity to cisplatin and oxaliplatin. Using the fluorescent cisplatin analog BODIPY-cisplatin, two-dimensional gel electrophoresis, and mass spectrometry, we identified the protein binding partners in A2780 and cisplatin-resistant A2780cis ovarian carcinoma, as well as in HCT-8 and oxaliplatin-resistant HCT-8ox colorectal cell lines. Vimentin, only identified in ovarian cancer cells; growth factor receptor-bound protein 2, only identified in colorectal cancer cells; and glutathione-S-transferase π, identified in all four cell lines, were further investigated. The effect of pharmacological inhibition and siRNA-mediated knockdown on cytotoxicity was studied to assess the relevance of these binding partners. The silencing of glutathione-S-transferase π significantly sensitized intrinsically resistant HCT-8 and HCT-8ox cells to cisplatin, suggesting a possible involvement of the protein in the resistance of colorectal cancer cells to the drug. The inhibition of vimentin with FiVe1 resulted in a significant sensitization of A2780 and A2780cis cells to cisplatin, revealing new possibilities for improving the chemosensitivity of ovarian cancer cells.
Highlights
Even in times of targeted- and immunotherapies, traditional chemotherapy, such as platinum drugs, remains a backbone in the treatment of various solid tumors [1]
We chose a fluorescent cisplatin analog tagged with boron-dipyrromethene (BODIPY-cisplatin, Figure 1, [21]) to detect potential protein binding partners of cisplatin
The cytotoxicity of BODIPY-cisplatin was much lower in colorectal cancer cells, both in the oxaliplatin-sensitive HCT-8 and oxaliplatin-resistant HCT-8ox cell lines, which are intrinsically resistant to cisplatin
Summary
Even in times of targeted- and immunotherapies, traditional chemotherapy, such as platinum drugs, remains a backbone in the treatment of various solid tumors [1]. The major drawback of platinum-based chemotherapy is inherent and acquired resistance [2,3]. Studies have shown that only small amounts of intracellular platinum reach the nucleus and can interact with DNA, leading to apoptosis [4]. The fate of cisplatin in the cytosol and the relevance of alternative binding partners for tumor cell sensitivity and resistance have not yet been fully elucidated. Cisplatin is the oldest platinum drug approved, and while it is very effective in many tumor entities, its use is limited by severe side effects, such as nephropathy and emesis, often leading to the
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