Studies On The Antitumor Activities And Mechnisms Of FW523-3

During the course of screening for novel immunosuppressants, FW523-3 was isolated and purified from the culture broth of a marine Micromonospora chalcea. Its physico-chemical properties and spectra showed FW523-3 to be identical with a known antitumor antibiotic, lipopeptide rakicidin B. Previous research showed that FW523-3 could inhibit the growth of L929 cells and significantly reduce the size of the cell nucleus, F-Actin volume and the number of mitochondrial membrane potential compaired with Paclitaxel . The objective of the present study was to evaluate the effect of FW523-3 on anti-tumor and elucidate its mechanism. We found that FW523-3 could inhibit the growth of EC109 cells, A549 cells, 95 D cells, SGC7901 cells, HeLa cells, HepG2 cells, Vero cells and 3T3 cells. The inhibition of cells growth was both in time-and dose-dependent manner to some extent. However, the effects of FW523-3 on the growth of CHO cells and SHEEC cells were not obvious. In addition, colony formation of EC109 cells were significantly suppressed by FW523-3 in dose-dependent manner. EC109 cells were stimulated with 0.5μg/ml, 0.25μg/ml, 0.125μg/ml FW523-3 forty-eight hours. The unclear border, smaller size, more secretory granule, refractive index decreased and conglobation of EC109 cells were observed under the microscope after treated with FW523-3. The result of DNA gel electrophoresis indicated that apoptosis was induced by FW523-3 and the rate of apoptosis was 19.22±1.02% evaluated by flow cytometry. Western blotting was performed to explain the mechanism of the apoptosis. The results showed that FW523-3 leaded to the activation of caspase-9, caspase-7 and caspase-3. The down-regulation of ERK1/2 , p38, p-ERK, CTGF and up-regulation of ATF3 and CYR61 were found after stimulating with FW523-3, but there was no effect on p-JNK. Besides, the reduction of radiative cytoskeleton and ability of cell adhersion was also found after treated with FW523-3. Taken together,These data suggest a model for anti-tumor in which FW523-3 acts through intrinsic apoptotic pathways, inhibited the expression of p38 and ERK, and alteration the cytoskeleton and adhersion.