NKH477 inhibits proliferation and induces apoptosis in a panel of cancer cell lines

The anti-proliferative effects of cAMP in cancer cells may be regulated by the adenylyl-cyclase-V isoform. As Colforsin Daropate [NKH477] is more selective for this isoform, we hypothesized that this water soluble compound may promise utility as an oral anti-tumour agent. Using separate cancer cell lines [MCF7, HT29, A431, WiDr, RKO, A375, H630, Du145, SW480 and SW620], we studied the effects of NKH477 on cell proliferation, cell viability and apoptosis. NKH477 induced >70% inhibition of proliferation in all cancer cell lines tested. NKH477 induced a dose-dependent apoptosis causing G1 arrest and priming cells to die. NKH477 treatment on the tested cell lines inhibited proliferation and induced apoptosis. Thus, NKH477 shows early promise as an oral anti-cancer agent

Programmed cell death of B lymphocytes is induced by ligation of integrin-associated protein [CD47]

As part of the Immunoglobulin [Ig] superfamily, the transmembrane glycoprotein CD47 forms a signalling complex with the CD23 receptor alphavbeta3 integrin, which stimulates cytokine synthesis and controls inflammation by regulating leukocyte activation and the phagocytosis of aging apoptotic leukocytes. To investigate the effects of anti-CD47 antibodies on a range of cell types at varying stages of development. Using flow cytometric analysis, KMS11 and H929 human B lymphocyte multiple myeloma cell lines were used to study the expression of CD47 and alphavbeta3 integrin as a means to explore the factors relating to the induction and resistance to apoptosis. We found that both cell lines expressed high levels of CD47, with KMS11 cells expressing more than H929 cells. CD47 stimulated an increase in apoptosis in both KMS11 and H929 cells with the preponderance being late apoptotic, dying cells. Ligation of CD47 via the soluble phase was crucial for apoptosis to take place. These results provided an insight into the apoptotic mechanisms involved in the control of inflammation surrounding the activation and phagocytosis of leukocytes. In conclusion, further analysis is required to elucidate the complete signaling cascade responsible for this proliferative effect. Induction of apoptosis via CD47 stimulation appears to occur in the absence of CD47's signaling complex partner, alphavbeta3 whether or not apoptosis occurs, appears to be dependent upon the cell type and also the way CD47 is engaged

TH 1/TH2 cytokine fingerprinting for probing diseases: from the bench to the clinic

Cytokines play crucial roles in all aspects of health and diseases. They influence immune expression, the development of immunologic memory, and regulation of antigen-specific and nonspecific immune activation. Based on their production by T helper [TH] cells, cytokines are categorized into TH1 and TH2 types. TH1 type includes inflammatory cytokines and growth factors. The former induces signal three that bridge innate and adoptive immunity, whilst the latter sustains proliferation and survival of T cells. Therefore, TH1 cytokines profoundly mediate generation of preventive immune responses toward infectious diseases and cancer. By contrast, TH2 cytokines are anti-inflammatory through suppression of TH1-mediated immune responses, but they also accelerate TH2-mediated diseases. This article describes the impact of the TH1/TH2 cytokines on shaping the nature of the immune cell responses to inflammation, infection, and cancer. We predict that TH1/TH2 could be considered as a fingerprint for probing the identity of diseases. Fundamental knowledge of the design of cytokine-based theropeutic strategies is now reaching the phase of application and a number of cytokines ore already on the market and many others are under clinical investigation