Immune checkpoint inhibitors as drugs or drug candidates in neoplastic diseases

Despite of great progress in anti-neoplastic treatment the several solid tumors and hematologic malignancies still remain incurable. Immune system remains under control of several controlling mechanism. Genetic or epigenetic changes in neoplastic cells provide antigen-derived diversity; however, these cells do not initiate immune response. The main mechanism of development of immune resistance by tumor cells seems to be a change in expression of proteins engaged in the immune control point. Immunotherapy with immune checkpoint inhibitors has emerged as promising modality of tumors showing response to several antigens, e.g. anti-CTLA-4 or PD1-PDL1 monoclonal antibodies. In this review we demonstrate the state in the field on this modality of anti-neoplastic treatment

Cytotoxic activity of R-amphinase, an anti-tumor endoribonuclease, on diffuse large B-cell lymphoma cells in conditions

Onconase (ONC) and R-Amphinase (R-AM) are enzymes with anti-tumor activity, belonging to pancreatic ribonuclease A family, received from eggs collected from frog Rana pipiens. Both proteins can induce death of some types of neoplastic cells by inhibition of protein synthesis, cell growth and proliferation. The aim of this study was to assess the cytotoxicity of R-AM, used alone or in combination with one of the most active anti-leukemic drug, doxorubicin (DOX), on diffuse large B-cell lymphoma (DLBCL)-derived cell line, Toledo. We found high cytotoxic activity of R-AM against DLBCL cells as well as influence on expression of several apoptosis-regulating proteins. Moreover, we observed increase in proapoptotic activity after combination of R-AM and DOX, compared with both drugs used alone. These results may justify further studies on interactions of R-AM with other drugs active in DLBCL

Pro-Apoptotic Activity of New Honokiol/Triphenylmethane Analogues in B-Cell Lymphoid Malignancies

Honokiol and triphenylmethanes are small molecules with anti-tumor properties. Recently, we synthesized new honokiol analogues (HAs) that possess common features of both groups. We assessed the anti-tumor effectiveness of HAs in B-cell leukemia/lymphoma cells, namely in chronic lymphocytic leukemia (CLL) cells ex vivo and in pre-B-cell acute lymphoblastic leukemia (Nalm-6), Burkitt lymphoma (BL; Raji), diffuse large B-cell lymphoma (DLBCL; Toledo) and multiple myeloma (MM; RPMI 8226) cell lines. Four of these compounds appeared to be significantly active against the majority of cells examined, with no significant impact on healthy lymphocytes. These active HAs induced caspase-dependent apoptosis, causing significant deregulation of several apoptosis-regulating proteins. Overall, these compounds downregulated Bcl-2 and XIAP and upregulated Bax, Bak and survivin proteins. In conclusion, some of the HAs are potent tumor-selective inducers of apoptosis in ex vivo CLL and in BL, DLBCL and MM cells in vitro. Further preclinical studies of these agents are recommended