Dihydroartemisinin can inhibit calmodulin, calmodulin-dependent phosphodiesterase activity and stimulate cellular immune responses

Calmodulin (CaM) is a ubiquitous, calcium-binding protein that regulates several important aspects of cellular metabolism. A number of enzymes such as phosphodiesterase (PDE-1) are stimulated by CaM. In previous studies, our results showed that artemisinin (ART) is a potent inhibitor of CaM and PDE-1 activity. In this study, the effects of dihydroartemisinin (DHA) that is a semisynthesized agent from the ART on CaM structure were investigated. The result showed that DHA increased fluorescence emission of CaM in higher amounts compared with the ART. Also, the effect of DHA on CaM-dependent PDE-1 activity was studied. Kinetic analysis of the DHA-CaM interaction showed that this agent competitively inhibited the activation of PDE-1 without affecting Vmax. Km values of PDE-1 in the presence of ART and DHA were 10 and 15 microM, respectively; DHA increased Km value in higher amounts compared with the ART. The Ki constants for ART and DHA were 10 microM and 7.3 microM, respectively. As a conclusion, CaM and CaM-dependent PDE-1 were inhibited by DHA more than ART. The data indicated that DHA could stimulate the delayed type hypersensitivity (DTH) against sheep blood cells in Balb/c mice and reduced the tumor growth in vivo against invasive ductal carcinoma in Balb/c mice.