The Investigation Of SM-1 On Antitumor Pharmacodynamics And Preliminary Mechanisms

The process of cancer is complex, multipathogeny, and multi-step. Cancer belongs to an abnormal cell disease of gene sequence and expression, as genomic instability,many types of cells have strong heterogeneity and anti-apoptotic ability.The imbalance of cell apoptosis and proliferation is more common. Therefore, the reactivation of the apoptotic signaling pathway is an ideal treatment in anti-tumor therapy. A large number of studies have shown that the occurrence of apoptosis is associated with the activation of Procaspase-3.But the activation of apoptosis pathway in cancerous cells are regularly blocked. So the concentrations of procaspase-3 in tumor cells are obviously higher than in normal cells. Therefore, the reactivation of procaspase-3 in apoptotic cascades on the final step is the promising anti-tumor therapeutic strategies. SM-1, a procaspase-3-activating compound, was screened by Shenzhen Institute of Xiangya Biomedicine. SM-1 is a small molecule compound targeting the activation of procaspase-3. The previous research proved that SM-1 has good anti-tumor activity. Hence, in the present study, we will investigate the antitumor activity of SM-1 in vitro and vivo and its preliminary mechanisms.Firstly, The cell apoptosis rate of BGC-823 and HCT116 were detected by flow cytometry. The FCM result showed that SM-1 can significantly induce apoptosis in HCT116 and BGC-823 cells in vitro. When the concentration of SM-1 is 8μM, the early apoptosis and late apoptosis rate of BGC-823 has reached 17.93% and 13.24%.Similarly, the early apoptosis and late apoptosis rate of HCT116 has reached 24.31%and 21.83%. Compared with the control group, Hoechst 33258 staining results indicated that the apoptotic cells were increased and nucleus were stained densely with higher concentration of SM-1. The changes of the mitochondrial membrane potential in BGC-823 were detected by flow cytometry. The results showed that SM-1can contribute to the decline of mitochondrial membrane potential of BGC-823. The results of Western Blot showed that SM-1 can activate Procapase-3 to Caspase-3 in a dose-dependent manner. the inhibitory effects of SM-1 on proliferation of tumor cells in vitro were evaluated by using MTT method. We found that different concentrations of SM-1 have significantly inhibitory activity on tumor cells and the range of IC50 is0.13μg / ml to 13.82μg / ml. while the range of Imax has reached 70.55% to 99.94%.Secondly, the animal experiments of SM-1 in vivo showed that SM-1 can inhibit the growth of xenograft and orthotopic tumors in nude mice, including BGC-823 xenograft tumor, COLO205 xenograft tumor, Hep G2 xenograft tumor and orthotopic tumors.In summary, SM-1 can attenuate the disease progress of xenograft and orthotopic tumor model of BGC-823, COLO205 and Hep G2 in nude mice.SM-1 can significantly inhibit the proliferation of 12 tumor cell in vitro and induce BGC-823 cells and HCT116 cell apoptosis. The mechanism is related to the activation of Procaspase-3 to Caspase-3.