Inhibition of tumor cell invasion and ErbB2/PI3K signaling pathways by the glutathione disulfide-mimetic NOV-002

Abstract #1:

NOV-002, a glutathione disulfide-mimetic, is in advanced clinical development for oncology indications. It is believed to act by modulating intracellular and cell surface redox status resulting in a pleiotropic pharmacologic profile. Here we report the ability of NOV-002 to inhibit the invasiveness of human tumor cells in vitro by suppressing the activation of a well-characterized, redox sensitive signaling pathway that is critical for tumor cell growth and invasion. In the Matrigel invasion assay, NOV-002 inhibited the invasion of a variety of human tumor cell lines including A549 (non-small cell lung), MDA-MB436 (breast), SKOV3 (ovarian) and HCT-15, HCT-116 and Colo205 (colorectal) in a dose-dependent manner with IC50s between 17.7mM and 91mM. In contrast, cell migration was only inhibited in the colorectal tumor cell lines suggesting that NOV-002 may affect pathways which are specific for invasion. 1 mM NOV-002 (the highest concentration tested in the invasion and migration assays) was not toxic to any of the tumor cell lines studied even after 72 hours of culture using MTT viability assay. These effects were shown to involve the suppression of ErbB2 and phosphoinositide-3 kinase (PI3K) pathways by NOV-002. Immunoblot analysis demonstrated that NOV-002 reduced the expression of the phosphorylated (active) forms of signaling proteins ErbB2 and PI3k, known to regulate tumor cell invasion in A549 and Colo205 cells, without affecting the total amount of these proteins. Activation of Akt and RhoA, downstream molecules of the ErbB2/PI3K pathway, was also inhibited by NOV-002. Thus in both A549 and Colo205 cell lines, the active form of both upstream (ErbB2 and PI3K) and downstream (Akt and RhoA) signaling proteins were suppressed by NOV-002 at concentrations between 30 mM and 1 mM in a dose-dependent manner. Inhibition was more pronounced at 24 hours post-exposure compared to 8 or 16 hours. In prostate cancer PC3 cells which are not affected by NOV-002 in the invasion assay, suppression of ErbB2/PI3K signaling pathway was not observed. Thus, inhibition of tumor cell invasion by NOV-002 may be due to the inhibition of the ErbB2/PI3K signaling pathway activation that controls this process. We have previous shown that ERp5, a member of the redox-regulated protein disulfide isomerase family, promotes tumor cell invasion by activating the ErbB2/PI3K pathway. Thus ERp5 may represent a direct target for NOV-002. These results also indicate that NOV-002 may have particular therapeutic benefit in the treatment of cancers that utilize ErbB2 and PI3K pathway activation.

I'll get them all posted and then try to explain some science.