Prostaglandin EP4 receptor signalling was shown to prevent B cell receptor (BCR)-mediated proliferation, and represents a novel strategy toward improving the therapy of B cell malignancies, known to be depend on BCR signals for survival. Chronic lymphocytic leukemia (CLL) is the most common haematological malignancy diagnosed in adults and is currently an incurable disease. In our previous research we have shown that selective EP4 receptor agonist, inhibited NF-?B signalling pathway, resulting in an increased caspase-mediated apoptosis of malignant B cells. The aim of this study was to evaluate the EP4 receptor as a potential target for the treatment of CLL (1, 2). Malignant B cells were isolated from whole blood obtained after informed consent from CLL patients. The expression of EP4 receptor was higher on CLL cells compared to lymphoblastoid cell lines (LCLs) obtained from healthy donors. EP4 receptor agonist PgE1-OH induced a concentration and time dependent cytotoxicity in all 151 CLL cells tested. The anti-cancer effects were mediated via EP4 receptor as evident from stronger cytotoxic effects of selective EP4 receptor agonist compared to endogenous ligand PgE2 and the fact that EP4 receptor antagonist prevented PgE1-OH induced apoptosis
B.04 Guest lecture
COBISS.SI-ID: 4572017Evaluation of the immunomodulatory effects of compounds is an important part of preclinical and toxicological evaluation of medicines. Hence, we established a novel in vitro test system for evaluation of immunotoxic and immunomodulatory properties of compounds based on lymphoblasotid cell lines, which we utilised to evaluate imunomodulatory properties of prostaglandin EP4 receptor agonist, PgE1-OH. Next, EP4 receptor was evaluated as a potential therapeutic target for the treatment of B-cell leukaemia and lymphoma. PgE1-OH reduced the activity of NF-?B in the Burkitt’s lymphoma cell line Ramos, which led to synergistic effects with bortezomib and doxorubicin. PgE1-OH also acted synergistically with monoclonal antibodies rituximab and ofatumumab, for which the induction of complement dependent cytotoxicity in vitro was first confirmed. PgE1-OH induced apoptosis in malignant lymphocytes B (EC50 = 13.53 µM, N = 151) isolated from whole blood of patients with the diagnosis of chronic lymphocytic leukaemia (CLL) after their informed consent was obtained. Of particular importance is the discovery that PgE1-OH acted selectively cytotoxic in vitro in CLL cells obtained from patients who are resistant to standard therapy and carry the deletion of the TP53 gene. Moreover, PgE1-OH acted synergistically with fludarabine, which might offer novel therapeutic options. In conclusion, EP4 receptor was evaluated as a promising therapeutic target for the treatment of B-cell leukaemia and lymphoma. COBISS ID: 4647537
E.01 National awards
COBISS.SI-ID: 4629617Evaluation of the immunomodulatory effects of the compounds is an important part of preclinical and toxicological evaluation of medicines. Hence, we established a novel in vitro test system for evaluation of immunotoxic and immunomodulatory properties of compounds based on lymphoblasotid cell lines, which we utilized to evaluate imunomodulatory properties of prostaglandin EP4 receptor agonist, PgE1-OH. Next, EP4 receptor was evaluated as a potential therapeutic target for the treatment of B cell leukemia and lymphoma. PgE1-OH reduced the activity of NF-?B in the Burkitt's lymphoma cell line Ramos, which led to synergistic effects with bortezomib and doxorubicin. PgE1-OH also acted synergistically with monoclonal antibodies rituximab and ofatumumab, for which the induction of complement dependent cytotoxicity in vitro was first confirmed. PgE1-OH induced apoptosis in malignant lymphocytes B isolated from whole blood of patients with diagnosis of chronic lymphocytic leukemia (CLL) after informed consent was obtained. Of particular importance is the discovery that PgE1-OH acted selectively cytotoxic in vitro in CLL cells obtained from patients, who are resistant to standard therapy and carry the deletion of the TP53 gene. Moreover, PgE1-OH acted synergistically with fludarabine, which might provide novel therapeutic options. In conclusion, EP4 receptor was evaluated as a promising therapeutic target for the treatment of B cell leukemia and lymphoma.
D.10 Educational activities
COBISS.SI-ID: 295575552