| Objective: Cancer is one of the diseases that mostly harmful to human health in theworld. The main means of cancer treatment is surgical resection, radiotherapy orchemotherapy. Surgical resection or radiotherapy is more successful for the early tumorpatients with no invasion and metastasis, but it is not ideal for patients with late tumors;Moreover, radiotherapy and chemotherapy also have a certain impact on the exuberantproliferation of normal cells while killing cancer cells, as a result, in vomiting, diarrhea,hair loss and bone marrow suppression and other adverse reactions, it seriouslyinfluenced the patients' life quality. In this study, effect of cepharanthine joint applicationwith chemotherapy drugs on inhibition of tumor were studied, and the possiblemechanism of cepharanthine raising organism immunity, inducing apoptosis of tumorcell and preventing invasion of tumor cell were approached in vivo and in vitro.Methods: The effects of cepharanthine on inhibition of tumor growth was studied byoral administration cepharanthine; It was identified whether cepharanthine has thesynergies on chemotherapy drug through the inhibit-tumor experiment of cepharanthinejoint application with chemotherapy drugs; The general pharmacology indicators ofcepharanthine on chemotherapy bearing-tumor mice was identified by detecting the levelof WBC, erythrocyte, serum ALT and BUN, etc. and the number of bone marrow cells; Itwas identified whether cepharanthine has synergistic effects on immune system throughanalyzing the effect of cepharanthine on spleen index, thymus index and the impact ofleukocyte DNA; Then, the effect of cepharanthine on invasion process in vitro of humanHT1080 fibrosarcoma cells was observed through adhesion analysis assay, scarificationassay, artificial reconstruction of the basement membrane experiment gelatinase spectrumanalysis, Western blotting and so on in vitro; Induction of cepharanthine on tumor-cellapoptosis was detected using acridine orange staining and flow cytometry; Impact ofcepharanthine on the malignancy extent of tumor cells was detected applyingcolony-forming. Results: The results show that: 1. Cepharanthine could dose-dependently inhibit thegrowth of transplanted solid tumors of mice, significantly extended life span ofbearing-tumor (S180), intraperitoneal injection of cepharatnhine (20 mg / kg body weight)could make inhibitory rate of U14 tumor weight reach 30.8% (P＜0.01); and inhibitoryrate of B16-F10 tumor weight reach 35.8% (P＜0.01). Compared with model group, lifespan of mice was extended at 42.6% (P＜0.01). When cepharanthine and CTX-jointapplied, antitumor activity was significantly increased (p＜0.01). Medium and high dosecepharanthine and CTX-joint application tumor inhibition rates (44.9% and 62.5 %) ishigher than that of CTX group (p＜0.05, p＜0.01); Medium and high dose cepharanthinecombined with CTX comparison to single CTX group, the peripheral red blood cells inmice could significantly increased (P＜0.01), 3.7% and 8.3% respectively. The peripheralhemoglobin in mice could significantly increased (P＜0.01), 7.3% and 9.1% respectively.Cepharanthine combined with CTX comparison to the normal group, the descentamplitude of white blood cells were less, but the difference was significant comparison toCTX group (P＜0.01); The mice spleen lymphocyte transformation rate were significantly(P＜0.01) increased compared with CTX group after cepharanthine combined with CTX,U14 tumor cell lines inoculation of mice, spleen index and thymus index oftumor-beating mice were significantly increased after cepharanthine combined with CTX(P＜0.01).Cepharanthine could dose-dependently prevent DNA damage induced bycyclophosphamide. The results indicated that cepharanthine has some attenuationsynergistic effect on anti-tumor of CTX.2. Cepharanthine could concentration-dependently inhibit tumor cell proliferation (2～40μM) to people fibrosarcoma cells HT-1080, hepatoma carcinoma cell SMMC7721, Helacells and so on. IC50 values of drugs on the tumor cells were 12.37±1.64μM, 12.58±1.05μM, 11.83±1.33μM respectively (treated for 48 hr); Moreover cepharanthinecould induce apoptosis of hepatoma carcinoma cell. Apoptotic cell was counted after theAO / EB stained, when SMMC7721 cells were dealed with 4μM cepharanthine for 48hours, the apoptosis rate can reach 24.7% (P＜0.01).3. Cepharanthine could inhibit tumor cell invasion and migration. Compared with thecontrol group, 4μM drug pretreatment 48 hours later, the invasiveness of HT1080 cellswas significantly decreased (p＜0.01). Moreover cepharanthine could dose-dependently inhibit the adhesion of tumor cell and basement membrane remarkably, weaken the motorability and invasiveness of tumor cell, reduce activity and expression quantity of MMP-2,up-regulate the expression of TIMP-2.4. Cepharanthine could lower malignancy extent with low concentration and longprocessing time, SMMC7721 cells was treated using cepharanthine 4μM for a long time,after treatment of 50 generations, the colony formation rate was decreased gradually, andcell doubling time was increased gradually.Conclusion: Cepharanthine could dose-dependently inhibit the growth of transplantedsolid tumors of mice, extended life span of bearing-tumor. It could play a certain synergiaand attenuation when combined with the chemotherapy drug cyclophosphamide. Themechanisms of cepharanthine inhibition tumor growth and tumor apoptosis is closelyrelated to its effect of inhibition tumor cell degradation basement membrane.Cepharanthine is expected to study and develop as a new type of anticancer drug. |
PDF Full Text Request