Structure Modification, Antitumor Activity Of CA-4and Anti-inflammatory Mechanism Research Of Tanshinones

As a tubulin inhibitor, Combretastatin A-4(CA-4) was first isolated from the bark of the South African tree Combretum caffrum by Pettit et al. in1989. CA-4can discriminate between normal vessels and tumor vessels and selectively disrupt the abnormal tumor vasculature, leading ultimately to vascular collapse. CA-4exhibits excellent anticancer properties by interfering with the dynamics of tubulin, in that CA-4inhibits the polymerization of tubulin by binding to the colchicine site, which results in cell mitotic arrest. However, the molecules act on the same binding site have been shown to destroy neovasculature, but are different from CA-4, this effect is observed close to the maximum tolerated dose. The maximal tolerated doses allow for plasma membrane concentrations of CA-4to reach micromolar range are compatible with the concentrations required for its effects on tubulin. However, CA-4is insoluble, unstable and very easy to translate into its trans-form of low activity, which limits its clinical application. In spite of it, CA-4has a simple structure, excellent anticancer activity, has no drug resistance and is easy for the structure modification. For all this reason, CA-4has recently been the subject of considerable interest from pharmaceutical chemists attempting to design new compounds capable of mimicking the bioactivityof C A-4.In recent years, pharmaceutical workers have been always studying on the structural modification of CA-4, in order to obtain some CA-4derivatives, which have good antitumor activity, solubility and stability. Therefore a series of novel CA-4derivatives, which contained a3’-O-substituted carbonic ether moiety, were synthesized and evaluated for their antitumor activities against four tumor cell lines, including MDA-MB-231, MCF-7, K562and A549cells. These derivatives exhibited clear antitumor activities, and CA-4E, in particular, showed the highest bioactivity of all of the derivatives tested against all four tumor cell lines, with with IC50values in the range of1to180nM. Based on its high bioactivity, CA-4E was subsequently selected to investigate the antitumor mechanism of these synthetic compounds. The cell cycle results demonstrated that CA-4E induced time-and dose-dependent G2/M arrest in a similar manner to CA-4, although its effect was more powerful than that of CA-4, and the apoptosis data showed that CA-4E induced cellular apoptosis in a dose-dependent manner.Taken together, these results suggest that CA-4E should be subjected to further investigation as a potential anticancer drug candidate.The Salvia miltiorrhiza Bungevar.alba, in the same genus with S. miltiorrhiza Bunge, is native to Laiwu and Taian of Shandong province, China. Its root is usually used as Danshen like that of S. miltiorrhiza, which is a traditional Chinese medicine for the treatment of cardiovascular disease. Especially, it has been used to treat patients with TAO at local clinics for more than one hundred years. Our group analyzed the bioactive components in S. miltiorrhizavar.alba root and found that the bioactive components in S. miltiorrhizavar.alba root and found that its primary constituents were similar to those in S. miltiorrhiza root, mainly composed of tanshinones and salvianolic acids.The Salvia miltiorrhiza Bungevar.alba has a unique effect on the treatment of TAO and the researchers have made a lot of research on its anti-inflammatory mechanism. However, the underlying mechanism is not fully understood. This study examined the anti-inflammatory effects of these tanshinone derivatives in detail.This study examined the anti-inflammatory effects of these tanshinone derivatives in human aorta endothelial cells (HAECs). HAECs were treated with TNF-a in the presence or absence of tanshinone I, cryptotanshinone, or15, 16-dihydrotanshinone I. The mRNA levels of IL-6, NF-κB, ICAM-1, and VCAM-1were analyzed by quantitative RT-PCR. Serum IL-6level was measure with an ELISA kit and ICAM-1level by immunocytochemical staining. The HAEC adhesion by inflammatory cells was assessed by BCECF/AM labeling assay. TNF-α induced overexpression of IL-6, NF-κB, ICAM-1, and VCAM-1in HAECs was suppressed by tanshinone I, cryptotanshinone, or15,16-dihydrotanshinone I to different extent. Tanshinones inhibited the adhesion of inflammatory cell onto HAECs and cellular ROS level. The action mode on TNF-α induced phosphorylation of ERK1/2differed among tanshinones. These results demonstrated the benefits of tanshinones on the vascular health.