| Cancer threatens to the human being, and thus the R&D of novel drugs for theprevention and treatment of cancer has become a major task. It has been demonstratedthat histone deacetylases (HDAC) play key roles in the regulation of genes, and itsdysfunction is considered to be related to the initiation and progress of the tumor.Therefore, HDAC have become the potencial taegets for the treatment of cancer.MS-275is a compound with the property of inhibiting HDAC. It has been tested inthe phaseⅡclinical trials for the treatment of leukemia and some solid tumors.Comparing with other similar compounds, MS-275possesses high specificity andselectivity to tumors. As a result, searching for the novel compounds targeting HDACattracts more and more attention.In this study, the inhibitions of serial synthetic compounds targeting HDAC on theproliferation of tumor cells were investigated in vitro. Based on the results in vitro,several compounds were investigated in vivo for their anti-tumor activities. The mainresulds are summarized as the following.In the in vitro experiment, more than eighty compounds were screened for theirinhibitory effects on the cultured tumor cells. The following human tumor cell lineswere used in the experiment: colorectal cancer (HT-29), breast tumor (MCF-7),promyelocytic leukemia (HL-60), lung adenocarcinoma (A549), epithelial carcinoma(Hela), prostate carcinoma (Du145), hepatocellular liver carcinoma (HepG2),erythromyeloblastoid leukemia (K562) and embryonic kidney (HEK293) cell lines.MTT assay was employed to evaluate the above effects of the compounds at theconcentration ranges of10-5,5×10-6,10-6,10-7,10-8mol/L. The contact time of thecompounds with the cells is48h or72h. It was shown that some tested compoundshave their IC50values reached at micromoles level, and several at less thanmicromoles level. These compounds include Ben-x09, Ben-x11, Ben-x18, Ben-x021,Ben-x022, Ben-x032, Ben-124, Beny-0018and Beny-0019etc. Some of them havethe activities of inhibiting HDAC corresponding to the effects of inhibiting theproliferation of the tumor cells.In the in vivo experiment, two compounds of Ben-124and Beny-0018were testedin the nude mice with cancer xenograft, respectively. For the establishment of the ricemodel with human cancer xenograft, the nude mice were subcutaneously injected with human MCF-7or A549cancer cells. When the tumors grow up to about50-100mm3,the mice were randomly allocated into the four groups: the vehicle control group, lowand high Ben-124dosed (25and50mg/kg body weight) groups, and MS-275(50mg/kg body weight) group. The animals were orally administrated with the vehicle,Ben-124or MS-275one time per day and for21days. During the treatment period,body weights and the tumor volumes of the mice were measured twice a week. Thetumor growth curve was drawn and the tumor inhibition rate was calculated when theexperiments were completed. For Beny-0018, it was only tested in the mouse modelof with human MCF-7cancer cells xenograft.The results showed that the growth of MCF-7or A549tumor xenograft in mice wassignificantly inhibited by MS-275with the inhibition ratios of55.0%or60.2%,respectively, however, Ben-124with that of22.9%or26.6%. Beny-0018exerted itseffect on the MCF-7tumor xenograft in mice with the inhibition ratio of57.5%.In conclusion, it was found that at least nine compounds have the inhibitionactivities for the tumor cells proliferation indicated by the in vitro screening. Thecompounds of Ben-124and Beny0018have the strong antitumor activities in vitro,but they exerted their poor inhibiton on the tumor grouth of the mice with MCF-7orA549tumor xenograft, which might be ascribed to the pharmacokinetic of Ben-124and Beny0018. |
