Authors : Da Yong Lu , En Hong Chen , Jing Yi Cao , Jing Bin Xu and Jian Ding
Abstract: Probimane (Pro), an anti-cancer agent first synthesized in China, is a bisdioxopiperazine derivative. Its parent compound Razoxane (ICRF-159, Raz), was developed in the UK and targets neoplasmic metastases in particular. We have discovered that in addition to the inhibition of metastasis, Pro and Raz have different anti-proliferative effects on tumor cells grown in vitro. This finding merits further investigation. In the present study, we have compared Pro and Raz in terms of the relationship between their anti-proliferative effects on tumor cells and their inhibition of hypotonic hemolysis and Calmodulin (CaM) action. We found that Pro decreases red cell lysis by hypotonic saline and inhibits the activity of CaM activated Ca++-Mg++-ATPase in a dose-dependent manner. The differences of anti-proliferative, antihemolytic and anti-CaM effects between Pro and Raz were parallel. Therefore, we propose that the anti-proliferative effects of Pro might operate through CaM inhibition and membrane protection, possibly sialic acid-mediated. Experiments on the effects of these drugs on the dynamics (substrate and time dependence) of red cell membrane CaM-activated Ca++-Mg++-ATPase lead to a new model for their anticancer effects: Pro might be a competitive antagonist of CaM affecting the substrate-product balance of one type of CaM-targeted enzymes-Ca++-Mg++-ATPases.
Da Yong Lu , En Hong Chen , Jing Yi Cao , Jing Bin Xu and Jian Ding , 2007. The Anti-Proliferative Effects of Probimane and Razoxane on Tumor Cells are Concomitant with Inhibition of Hemolysis and Calmodulin (CaM) Action and a New CaM-ATPase Acting Model. Research Journal of Biological Sciences, 2: 127-133.