Combined Action of Anti-MUC1 Monoclonal Antibody and Pyrazole-Platinum(II) Complexes Reveals Higher Effectiveness towards Apoptotic Response in Comparison with Monotherapy in AGS Gastric Cancer Cells

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.

Anti-cancer effects of pyrazole-platinum(II) complexes combined with anti-MUC1 monoclonal antibody versus monotherapy in DLD-1 and HT-29 colon cancer cells

“…Substitution of pyrazole ring with ethyl group (PtPz6) occurred to be the most sufficient in apoptosis induction, especially when applied with anti-MUC1 mAb. Similar results concerning apoptotic response have been revealed in gastric cancer cells when the same therapy was applied [36] .…”

“…Applying cisplatin derivatives and combining the chemotherapeutic with other drugs have been greatly regarded to conquer drug-resistance and minimize toxicity [34] . Recently, two novel pyrazole-platinum(II) complexes PtPz4 ([Pt 2 (pyrazole) 4 (berenil) 2 ]•4HCl•2H 2 O) and PtPz6 ([Pt 2 (N-ethylpyrazole) 4 (berenil) 2 ]•4HCl•2H 2 O), combined with anti-MUC1 monoclonal antibody, have been examined against breast [10] and gastric [36] cancer cells. It was revealed that cisPt derivatives, administrated with mAb, occurred to be more effective than monotherapy.…”

“…Recently we have revealed that application of anti-MUC1 as well as mAb combined with PtPz4, PtPz6 and cisPt in AGS gastric cancer cells inhibited the expression of TACAs (mucin-type, tumor-associated carbohydrate antigens) commonly overexpressed on MUC1 mucin and on the surface of cancer cells [36] . They are markedly distributed in large number of tumors, but, what is especially important, not on normal cells [21] .…”

“…Recently, pyrazole-platinum complexes has been revealed as promising, anti-cancer agents in breast cancer cells [10] . Potential, anti-cancer action of such platinum derivatives combined with anti-MUC1 mAb has been also demonstrated in AGS gastric cancer cells [36] . In the present study we compared the effectiveness of monotherapy with combined therapy against selected apoptosis-related factors and specific cancer-associated sugar antigens likely participating in cancer development.…”