oxadiazoles and Carcinoma--Lewis-Lung

Indoleamine-2,3-dioxygenase 1 (IDO1), which catalyzes the degradation of L-tryptophan (L-Trp) to N-formyl kynurenine (NFK) in the first and rate-limiting step of Kynurenine (KYN) pathway has been identified as a promising therapeutic target for cancer immunotherapy. The small molecule Epacadostat developed by Incyte Corp is the most advanced IDO1 inhibitor in clinical trials.. In this study, various amidine derivatives were individually installed as the polar capping group onto the amino ethylene side chain to replace the sulfamoylamino moiety of Epacadostat to develop novel IDO1 inhibitors. A series of novel 1,2,5-oxadiazol-3-carboximidamide derivatives were designed, prepared, and evaluated for their inhibitory activities against human IDO1 enzyme and cellular IDO1.. In vitro human IDO1 enzyme and cellular IDO1 assay results demonstrate that the inhibitory activities of compound 13a and 13b were comparable to Epacadostat, with the enzymatic IC50 values of 49.37nM and 52.12nM and cellular IC50 values of 12.34nM and 14.34nM, respectively. The anti-tumor efficacy of 13b is slightly better than Epacadosta in Lewis Lung Cancer (LLC) tumor-bearing mice model.. 13b is a potent IDO1 inhibitor with therapeutic potential in tumor immunotherapy.

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; HeLa Cells; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Neoplasms, Experimental; Oxadiazoles; Structure-Activity Relationship

FTY720, a sphingosine 1-phosphate (S1P) analog, acts as an immunosuppressant through trapping of T cells in secondary lymphoid tissues. FTY720 was also shown to prevent tumor growth and to inhibit vascular permeability. The MTT proliferation assay illustrated that endothelial cells are more susceptible to the anti-proliferative effect of FTY720 than Lewis lung carcinoma (LLC1) cells. In a spheroid angiogenesis model, FTY720 potently inhibited the sprouting activity of VEGF-A-stimulated endothelial cells even at concentrations that apparently had no anti-proliferative effect. Mechanistically, the anti-angiogenic effect of the general S1P receptor agonist FTY720 was mimicked by the specific S1P1 receptor agonist SEW2871. Moreover, the anti-angiogenic effect of FTY720 was abrogated in the presence of CXCR4-neutralizing antibodies. This indicates that the effect was at least in part mediated by the S1P1 receptor and involved transactivation of the CXCR4 chemokine receptor. Additionally, we could illustrate in a coculture spheroid model, employing endothelial and smooth muscle cells (SMCs), that the latter confer a strong protective effect regarding the action of FTY720 upon the endothelial cells. In a subcutaneous LLC1 tumor model, the anti-angiogenic capacity translated into a reduced tumor size in syngeneic C57BL/6 mice. Consistently, in the Matrigel plug in vivo assay, 10 mg/kg/d FTY720 resulted in a strong inhibition of angiogenesis as demonstrated by a reduced capillary density. Thus, in organ transplant patients, FTY720 may prove efficacious in preventing graft rejection as well as tumor development.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Lewis Lung; Cell Division; Cells, Cultured; Coculture Techniques; Collagen; Drug Combinations; Endothelium, Vascular; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Laminin; Mice; Mice, Inbred C57BL; Muscle, Smooth; Neoplasm Transplantation; Neovascularization, Pathologic; Neutralization Tests; Oxadiazoles; Propylene Glycols; Proteoglycans; Receptors, CXCR4; Receptors, Lysosphingolipid; Sphingosine; Thiophenes; Transcriptional Activation; Transplantation, Isogeneic; Umbilical Veins; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

To investigate the inhibitory effect of a new compound of GLB on tumor metastasis in vivo and analyze its actions on tumor cell adhesion to clarify its mechanism.. The effect of GLB on tumor metastasis was analyzed by Lewis lung carcinoma model. The pathological morphology of lung alveolar was evaluated by hematoxylin-eosin staining. The effect of GLB on the proliferation of human prostate cancer cell (PC-3M, with a high metastatic characteristic) was studied using the MTT method, and its actions on PC-3M cell adhesion to human umbilical vein endothelial cells (HUVEC) and laminin were analyzed in vitro.. GLB (100 mg/kg/d for 28 d, ig) reduced the number of lung colonies of Lewis lung carcinoma metastasis significantly (P<0.05). Simultaneously, GLB could mitigate the damage of lung alveolar caused by metastasic tumor deposits. In vitro, GLB inhibited dramatically the adhesion of PC-3M cells to HUVEC (P< 0.01) and laminin (P<0.05), without cytotoxic or anti-proliferative action on PC-3M cells.. GLB has anti-tumor metastatic activity, which partly depends on its inhibition of tumor adhesion.

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Endothelial Cells; Female; Humans; Laminin; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Neoplasm Metastasis; Neoplasm Transplantation; Oxadiazoles; Prostatic Neoplasms; Pyrans; Spiro Compounds; Umbilical Veins