Abstract
MUC1 mucin is a transmembrane glycoprotein aberrantly overexpressed and underglycosylated in most epithelium origin cancers. Combining chemotherapeutics with monoclonal antibodies toward cancer-related antigens is one of the new strategies in cancer therapies. In this study, we assessed the effectiveness of 10 μM cisplatin (cisPt), two pyrazole-platinum(II) complexes (PtPz4 and PtPz6), and 5 μg/mL anti-MUC1 used as monotherapy, as well as cisplatin and its derivatives combined with mAb on apoptotic response and specific cancer-related sugar antigens in AGS gastric cancer cells. Flow cytometry, RT-PCR, Western blotting, and ELISA tests were applied to determine the influence of examined compounds on analyzed factors. PtPz6 combined with anti-MUC1 revealed the strongest apoptotic response compared to control and monotherapy. The combined action of both cisPt derivatives and anti-MUC1 was more effective than monotherapy in relation to Bad, Bcl-xL, Bcl-2, caspase-9, caspase-3, as well as pro- and cleaved caspase-3 protein, and T, sialyl Tn sugar antigens in cell lysates, and Tn, T, sialyl Tn, sialyl T antigens in culture medium. Additionally, PtPz4 administrated with mAb was revealed to be more potent than used alone with regard to Bax protein and Bid expression, and PtPz6 used in complex with anti-MUC1 revealed more efficient action towards Akt and sialyl T antigen expression. These data indicate the rationality of the potential application of combined treatment of anti-MUC1 and cisPt derivatives in gastric cancer therapy.
Highlights
Gastric cancer (GC) has been stated as one of the leading causes of tumor-related deaths globally [1]
We found that cisplatin used alone and in combination with anti-mucin 1 (MUC1) significantly increased mucin cytoplasmic domain expression (Figure 4)
Rest of the examined compounds used in monotherapy andtha co cisPt, and anti-MUC1 when used alone, andon cisPtThese combined with mAb with anti-MUC1 had no significant impact
Summary
Gastric cancer (GC) has been stated as one of the leading causes of tumor-related deaths globally [1]. Its action in cancer cells is based on the potential to crosslink with the DNA purine bases, attenuating DNA repair, leading to DNA damage, and inducing apoptosis. Its usage can be limited by its severe side effects, as neurotoxicity, anaphylaxis, cytopenias, and others. Resistance to this drug can reduce its application in many tumors [4,5]. In the last years, numerous platinum-based compounds were synthesized with the goal of reducing adverse effects and overcoming drug resistance [6]. Recent studies on breast cancer cells revealed that pyrazole-platinum(II)
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