| The malignant tumor has become one of the factors are seriously harmful to human health at present. Breast cancer and HCC are the prevalent diseases and they are too aggressive and resistant to treat. The development of new effective drugs is an important concern. Recently, it has been reported that the introduction of heteroatoms in the benzene ring of the nucleus may modulate the binding capacity of small molecules to kinases and improve the antitumor activity. HD-ZWM-288 was one of bisindolylmaleimide compounds exhibited potent activity that displayed a substantial inhibitory effect on the viability of cancer cells, and firstly discussed interestingly.Previous studies indicated that HD-ZWM-288 exhibited nice interuption in microtubule system. MTT assay showed that it suppressed cancer cells prolifiration (the IC50 of HD-ZWM-288 for 48h to MCF-7 and MDA-MB-231 were 0.62 and 2.06 μM, respectively). It also exert excellent anticancer activity in xenograft study. The results of IF, Western Blot and IHC showed that HD-ZWM-288 could depressed microtubules depolymerization. We also found HD-ZWM-288 induced G2/M phase arrest in both cells. During delayed exposure of HD-ZWM-288, we could found that it induced apoptosis demonstrated by DAPI and flow cytometry, respectively. In conclusion, HD-ZWM-288 suppresses the growth of the two breast cancer cells via depressing microtubules depolymerization, eventually induced cells arrest in G2/M phase and apoptosis with concentration dependence.Liver cancer is currently one of the world’s major cause of death and its development needs that the cell’s apoptosis and proliferation in a stable balance. MTT assay showed that HD-ZWM-288 reduced HepG-2 cells viability (the IC50 of HD-ZWM-288 for 48h to HepG-2 were 0.59 μM) and also exert anticancer activity in vivo HepG-2 xenograft study. HD-ZWM-288 suppressed the phosphorylation of cdc2 and increased the expression of Cyclin B1, so induced G2/M phase arrest then apoptosis in HepG-2 cells. Phosphorylation of H2AX was used for estimating DNA damage, and which increased in HepG-2 cells after exposed to the compound. In addition, generated ROS and the loss of MMP, deceased expression of Bcl-2 /Bax, and the release of Cytochrome C were also observed in HD-ZWM-288-treated HepG-2 cells. Further experiments demonstrated that it could triggered caspase cascade. In conclusion, HD-ZWM-288 suppressed the growth of HepG-2 cells via inducing DNA damage, mediating G2/M phase arrest and apoptosis.Angiogenesis is one of the most indispensable factor for primary tumor growth, invasiveness and for development of metastasis, which used for transporting the nutriment and oxygen that the cancer cells need and carring out the waste products they released. In this study, the effects of HD-ZWM-288 on anti-angiogenesis were investigated. The ability of migration and tube formation of HUVEC cells was markedly inhibited after exposure to HD-ZWM-288 in a somewhat lower concentration. The results of CAM and IHC showed it had a considerable antiangio gene sis activity in vivo. Furthermore, HD-ZWM-288 could inhibit secretion of MMP-2 and its activity and down-regulated VEGF. Moreover, the expression of p-ERK1/2 and p-Akt changed at different levels after treatment of HD-ZWM-288. These findings made it clear that HD-ZWM-288 could inhibit angiogenesis by decreasing the VEGF-mediated MAPK and Akt pathway.In summary, HD-ZWM-288, a new bisindolymaleimide derivative which was firstly explored to have the activity against in a few of human cancer cells. The underlying anticancer mechanism of HD-ZWM-288 was also demonstrated for the first time. As a valid leading compound or therapeutic agent against cancer, HD-ZWM-288 should be worth to going a step further reseach. |
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