ABSTRACT
Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R+ cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer.
Subject(s)
Adenocarcinoma/drug therapy , Angiogenesis Inhibitors/therapeutic use , Colonic Neoplasms/drug therapy , M Phase Cell Cycle Checkpoints/drug effects , Mitosis/drug effects , Neovascularization, Pathologic/drug therapy , Phenylenediamines/therapeutic use , Quinolines/therapeutic use , 3T3 Cells , Animals , Aurora Kinase B/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Histones/metabolism , Humans , Inflammation/drug therapy , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Docking Simulation , Naphthalenes , Phosphorylation/drug effects , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To analyze the clinical course of a very elderly patient with advanced diffuse large B cell lymphoma (DLBCL), so as to explore the incidence, prognosis and treatment of DLBCL and to analyse the prognostic and therapeutic significance of molecular subtype. METHODS: The clinical history, auxiliary examinations, clinical diagnostic standards, therapeutic methods, biopsy and autopsy of this patient were retrospectively analyzed; the incidence, current treatment status, molecular biological features, and prognostic and therapeutic significance of molecular subtype were studied. RESULTS: After admission, this patient was diagnosed as non-GCB DLBCL, NOS, stage IV B and in the high risk group (IPI = 5, ECOG = 2). She achieved a decent partial response after many times of imunochemotherapy, but his disease status soon progressed. The liver occupying biopsy revealed non-GCB, while the spleen tumor pathology revealed GCB; pathological typing of these two methods was completely opposite. Autopsy pathological diagnosis showed that the death causes included extensive tumor metastasis, dyscrasia and respiratory circle failure. CONCLUSION: Incidence of aged patients with DLBCL is high, and the disease is aggressive; the treatment is low responsive and difficult, and new therapeutic methods are needed. Gene expression profile (GEP) can provide molecular subtype and potential pathogenic mechanism, which can promote the development of new targeted therapy and individualized treatment.
Subject(s)
Lymphoma, Large B-Cell, Diffuse/diagnosis , Aged , Female , Humans , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/therapy , Neoplasm Staging , PrognosisABSTRACT
AIM: To compare the effect of the two types of TNF-alpha, transmembrane TNF-alpha (TM-TNF-alpha) and secreted TNF-alpha (sTNF-alpha) on the biological functions of monocytic cell line U937 so as to explore the role of TM-TNF-alpha in inflammation. METHODS: Effect of the two types of TNF-alpha on the functions of U937 cells, such as phagocytosis, accumulation of cytokines' mRNA, the level of cytoplasmic IkappaB-alpha and expression of ICAM-1, was compared by phagocytosis, RT-PCR, Western blot and FACS. RESULTS: sTNF-alpha was found to be able to promote markedly phagocytosis by monocytic U937 cells, enhance the mRNA accumulation of cytokines, such as TNF-alpha, IL-1beta and IL-8 mRNA, induce the degradation of IkappaB-alpha and the expression of adhesion molecule ICAM-1; while TM-TNF-alpha was shown to have no effect on the functions above of U937 cells. Furthermore, it seemed TM-TNF-alpha did not have a synergic action with sTNF-alpha when U937 cells was treated with both types of TNF-alpha. CONCLUSION: The data above shows that sTNF-alpha can activate U937 cells, while TM-TNF-alpha has no influence. It suggests that the two types of TNF-alpha may play the different role in inflammation.