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Cinobufacini is an extract from skin of Bufo gargarizans, and composed of bufadienolides, peptides, alkaloids and cholesterol. With the deepening of research of its pharmacological effect, it has been proved that cinobufacini has important application value in anti-inflammation, anti-virus, anti-tumor, as well as swelling and pain relief. In recent years, more attention has been given to its anti-tumor activity. The molecular pharmacology studies showed that cinobufacini plays an important role on anti-tumor by enhancing the immunity, inhibiting the proliferation of tumor cells, inducing the apoptosis of tumor cells, reversing multidrug resistance of tumor cells, and inhibiting the tumor angiogenesis. Both intrinsic pathway mediated by mitochondria and extrinsic pathway mediated by death receptor are involved in cinobufacini-induced apoptosis. Clinical studies have shown that cinobufacini is broadly used as an anti-tumor traditional Chinese medicine, due to its advantages of low toxicity, less side effects, and wide anticancer spectrum. It is broadly used in the treatment of liver cancer, gastric carcinoma, lung cancer, colon cancer, esophageal carcinoma, carcinoma of gallbladder, and non-Hodgkinlymphoma. Either single or combined application plays an active role in improving the efficacy and reducing side effects. To promote the research of anti-tumor activity of cinobufacini, and expand its application prospects, this review focuses on anti-tumor mechanism and clinical application of cinobufacini.
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To systemically evaluate the efficacy and safety of Cinobufacini Injection in combination with platinum-contained first-line chemotherapy for treatment of non-small cell lung cancer(NSCLC). The randomized controlled trials(RCT) about the Cinobufacini in combination with platinum-contained first-line chemotherapy(versus chemotherapy alone) were collected through PubMed,Cochrane library,CNKI,VIP,CBM,and Wan Fang Database from database inception to December 2018. Two researchers extracted data and assessed the literature quality separately,and made a Meta-analysis by using Rev Man 5. 3 software. Twenty-seven RCTs were included in the present review,involving 2 125 patients,1 082 in treatment group and 1 043 in control group. The Meta-analysis results showed that as compared with chemotherapy alone,the combination of Cinobufacini and platinum-contained first-line chemotherapy could enhance one year survival rate(RR = 1. 34,95%CI[1. 17,1. 55],P< 0. 01),two year survival rate(RR = 1. 84,95% CI[1. 31,2. 59],P<0. 01),objective tumor response rate(RR = 1. 47,95%CI[1. 33,1. 63],P<0. 01); improve the quality of life for patients(RR =1. 54,95%CI[1. 37,1. 72],P < 0. 01); and reduce the incidences of WBC toxicity(RR = 0. 63,95% CI[0. 49,0. 80],P < 0. 01),platelet toxicity(RR = 0. 54,95%CI[0. 35,0. 84],P<0. 01),gastrointestinal reactions(RR = 0. 60,95%CI[0. 45,0. 80],P<0. 05),pain(RR = 1. 68,95% CI[1. 38,2. 03],P< 0. 01),and hair loss reaction(RR = 0. 76,95% CI[0. 59,0. 98],P < 0. 05). The results showed that for the treatment of NSCLC,the addition of cinofacini to conventional platinum-contained chemotherapy can increase the long-term and short-term efficacy of chemotherapy,improve the quality of life for patients,and reduce the side effects of platinumbased chemotherapy drugs. However,more high quality and large-scale randomized controlled trials are required to verify this conclusion in the future.
Subject(s)
Humans , Male , Amphibian Venoms/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Platinum/chemistry , Quality of LifeABSTRACT
Objective To observe the therapeutic effect of the combination of cinobufacini with DC chemo-therapy in the treatment of advanced stomach cancer .Methods 65 patients who were diagnosed advanced gastric cancer on the basis of histocytology and pathology results , were randomly divided into DC chemotherapy group (31 cases) and combined treatment group (34 cases).The clinical curative effect ,adverse reaction,quality of life ( KPS questionnaire ) and the easement rate of pain were analyzed .Results The two groups had no statistically significant differences in adverse reaction (t=-0.0047,P>0.05) and clinical curative effect (χ2 =0.077,P>0.05),and the clinical response rate of the combined treatment group (35％) was similar to the DC chemotherapy group (32％).Besides,the easement rate of pain in the combined treatment group increased to 71％,which in the DC chemotherapy group increased to 45％(χ2 =19.969,P<0.05).And the improvement rate of quality of life (QOL) in the combined treatment group was 82％,which of the DC chemotherapy group was 55％,the difference was statistically significant(χ2 =13.923,P<0.05).Conclusion Cinobufaconi combined with DC chemotherapy in the treatment of advanced stomach cancer has no significant effect on increase of short -term efficacy ,but it can improve quality of life and alleviate pain obviously .
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Objective To investigate the effects of cinobufacini on TGF-β1-induced epithelial-to-mesenchymal transition of human colorectal carcinoma cells in vitro.Methods The cultured colorectal carcinoma cell line(SW480) was divided into the control group,TGF-β1 (10 ng/mL) individual treatment group and co-treatment groups with TGF-β1 (10 ng/mL) + cinobufacini (2.5,5,10,20,40,80 mg/mL),which were cultured in vitro for 48 h.The proliferation of the cells were measured by CCK8 assay.The morphological changes were observed by inverted phase contrast microscope.The ability of cell invasion and migration was detected by Transwell assay.The mRNA and protein expressions of E-cadherin and Vimentin were detected with QRT-PCR and Western Blot.Results (1)Compared with the TGF-β1 (10 ng/mL) individual treatment group,TGF-β1 (10 ng/mL) + cinobufacini (10,20,40,80 mg/mL) co-treatment groups significantly had significantly proliferation inhibitory effect on SW480 (P＜0.05).(2) Compared with the normal control group,TGF-β1 individual treatment group and TGF-β1 (10 ng/mL) + cinobufacini(2.5 mg/mL) group exhibited classical mesenchymal phenotype,while the TGF-β1 (10 ng/mL) + cinobufacini (5 mg/mL) co-treatment group showed classical epithelial phenotype.(3) The ability of invasion and migration in the TGF-β1(10 ng/mL)+ cinobufacini(2.5,5 mg/mL) co-treatment group were significantly weakened compared with the TGF-β1 individual treatment group (P＜0.01).(4) QRT-PCR and Western Blot results indicated that compared with the normal control group,the Vimentin expression in the in the TGF-β1 individual treatment group was significantly increased and the E-cadherin expression was significantly decreased.Furthermore,compared with the TGF-β1 individual treatment group and control group,the Vimentin expression level in the TGF-β1 (10 ng/mL) + cinobufacini (2.5,5 mg/mL) groups was significantly decreased and E-cadherin expression was significantly increased.Conclusion Cinobufacini can inhibit TGF-β1-induced cell proliferation in human colorectal carcinoma SW480 cells,and its mechanism may be related with promoting E-cadherin expression increase,meanwhile decreasing the vimentin expression,thus inhibiting the EMT process induced by TGF-β1.
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OBJECTIVE:To observe therapeutic efficacy and safety of cinobufacini capsules combined with paclitaxel and cisplatin in the treatment of middle and advanced cervical cancer.METHODS:A total of 92 patients with middle and advanced cervical cancer were randomly divided into observation group (46 cases) and control group (46 cases).Both groups received pelvic intensity-modulated radiotherapy (IMRT)+interstitial brachytherapy.Control group was additionally given Paclitaxel injection 135 mg/m2,d1+Cisplatin injection 75 mg/m2,d1,21 d as a treatment course,and received chemotherapy for 2 cycles since the fnrst day of radiotherapy.Observation group was additionally given Cinobufacini capsules 0.5 g orally since the first day of radiotherapy,3 times a day,until the end of radiotherapy.Clinical efficacies as well as platelet count,KPS score,body weight,pain relief and the recovery of platelet abnormality were observed in 2 groups,and the occurrence of toxic reaction was recorded.RESULTS:The complete remission rate,the rate of platelet count abnormality recovery as well as remission rate and total remission rate of pain after 3 weeks of treatment in observation group were significantly higher than control group,with statistical significance (P＜0.05).There was no statistical significance in the total response rate and remission rate after 4,5 weeks of treatment between 2 groups (P＞0.05).After treatment,platelet count of 2 groups were significantly lower than before,and the observation group was significantly lower than the control group;KPS score of 2 groups and body weight of observation group were significantly higher than before treatment;body weight of control group was significantly lower than before,and the observation group was significantly higher than the control group,with statistical significance (P＜0.05).The incidence of grade Ⅲ-Ⅳ neutropenia,nausea and vomiting,grade Ⅰ-Ⅱ diarrhea in observation group were significantly lower than control group,with statistical significance (P＜0.05).CONCLUSIONS:Based on conventional treatment,cinobufacini capsules combined with paclitaxel and cisplatin show significantly therapeutic efficacy for middle and advanced cervical cancer,improve blood hypercoagulation and survival quality,relieve pain and reduce the occurrence of toxic reaction.
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Objective To explore the clinical curative effect on non-small cell lung cancer (NSCLC) patients by cinobufacini injection combined with first-line chemotherapy.Methods Eighty patients with NSCLC from January 2013 to January 2015 in our hospital were selected as the research objects.Then they were divided into the observation group (n =40)and the control group (n =40)by random number tables.The patients in control group accepted docetaxel and cisplatin combination chemotherapy regimens (TP).While the observation group accepted cinobufacini injection on the basis of the control group.Then the local control, adverse reactions and prognosis of the two groups were compared.Results The local control of observation group was 77.5%,while the control group was 62.5%,the local control of observation group was obviously higher than that of the control group (χ2 =5.36,P =0.03).Leucopenia incidence of the observation group was 27.5%,the control group was 50.0%,and the incidence of the observation group was obviously lower than that of the control group (χ2 =4.27,P =0.04).There was no statistically significant difference between the two groups in diarrhea,stomachache,vomiting,tinnitus (17.5% vs.27.5%,χ2 =1.15,P =0.28;25.0% vs.45.0%,χ2 =3.52,P =0.06;5.0% vs.7.5%,χ2 =0.34,P =0.56;7.5% vs.10.0%,χ2 =0.16,P =0.69).There was statistically significant difference between the two groups in median survival time (97 d vs.45 d,HR =8.934,χ2 =9.928,P <0.05).Conclusion The cinobufacini injection combined with docetaxel can effectively reduce the incidence of myelosuppression,and improve survival and local control with high safety,and the clinical effect is remarkable and can improve the prognosis of patients.
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OBJECTIVE:To observe the clinical efficacy and safety of Cinobufacini capsule in the treatment of tumor patients with intractable hiccup. METHODS:120 tumor patients with intractable hiccup were randomly divided into observation group(60 cases) and control group (60 cases) according to the random number table. Control group received conventional treatment,treat-ment of primary disease,and the basic treatment of Methoxy metoclopramide tablets 10 mg,tid and intraorbital pressure on neural network method;observation group additionally received Cinobufacini capsule,2 capsules once,3 times a day. 1-week was regard-ed as a treatment course,and it lasted 4 courses. Clinical efficacy,Karnofsky functional status(KPS)score and disappearance time of hiccup were observed,and the incidence of adverse reactions was evaluated by TESS scale. RESULTS:After treatment,the to-tal effective rate in observation group was significantly higher than control group,the disappearance time of hiccup and TESS score were significantly shorter than control group,the differences were statistically significant(P<0.05). Before treatment,there was no significant difference in the KPS score;after treatment,the KPS score in 2 groups was significant higher than before,and observa-tion group was higher than control group,the difference was statistically significant(P<0.05). CONCLUSIONS:Both efficacy and safety of Cinobufacini capsule in the treatment of intractable hiccup are good,and it can shorten hiccup duration.
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OBJECTIVE:To observe clinical efficacy and toxic reaction of bronchial artery infusion(BAI)chemotherapy com-bined with Cinobufacini capsule in the treatment of advanced non-small cell lung cancer(NSCLC). METHODS:A total of 126 cas-es of advanced NSCLC diagnosed in stage Ⅲb-Ⅳ were randomly divided into observation and control group,63 cases in each group. Both of them were treated by BAI with taxotere/cisplatin(TP regimen),once every three weeks for a cycle,a total of 5 cy-cles;observation group was additionally given Cinobufacini capsule 500 mg/time,three times a day,on the basis of BAI chemo-therapy,for 15 weeks. Clinical efficacy,KPS,survival rate and toxic reaction of 2 groups were observed. RESULTS:The total ef-fective rate(82.54%)of observation group was better than that(63.49%)of control group,with statistical significance(P<0.05). KPS score of observation group was significantly better than that of control group,with statistical significance (P<0.05). 1-year survival rate of observation group and control group were 65.08% and 30.15%,2-year survival rate of them were 19.05% and 4.76%,with statistical significance(P<0.05). Adverse reactions of two groups was mainly marrow suppression and gastrointesti-nal reaction,marrow suppression degree and the incidence of nausea and vomiting in observation group was lighter than control group,with statistical significance (P<0.05). CONCLUSIONS:BAI combined with Cinobufacini capsule in the treatment of ad-vanced NSCLC can improve short-term curative effect and long-term survival rate,and can improve the survival quality with little toxic effect.
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Objective To observe the clinical curative effect of cinobufacini injection in the treatment of primary bronchopulmonary carcinoma.Methods 120 patients with primary bronchopulmonary carcinoma were randomly divided into the control group and treatment group,60 cases in each group.Patients of the control group were treated with the general,symptomatic and dialectical therapy.Patients of the treatment group were given general,symptomatic,dialectical treatment and cinobufacini injection.The curative effect was determined by the standard efficacy of tumor,the survival quality of the patients was judged by the Karnofsky score.The adverse reactions,median survival time and the survival rate were compared between the two groups.Results The effective rate of the control group was 40.0％,that of the treatment group was 56.7％,the difference was statistically significant (x2 =4.034,P ＜ 0.05).By the Karnofsky score,27 patients of the control group were stable,39 patients of the treatment group were stable,the difference was statistically significant(x2 =12.265,P ＜0.05).Median survival time of the control group was (168 ± 16) d,that of the treatment group was (178 ± 20)d,the difference was statistically significant(x2 =12.265,P ＜ 0.05).One year survival rates of the control group and the treatment group were 5.0％,10.0％,the difference was statistically significant.There was no statistically significant difference between two groups in adverse reactions (P ＞ 0.05).Conclusion Cinobufacini injection can improve the quality of life and prolong survival of patients with primary bronchopulmonary carcinoma.It is effective and safe in clinical application.
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OBJECTIVE: To study the effect of cinobufacini injection on proliferation, migration and tube-like structure formation of human hepatoma HepG-2 cells co-cultured with human lymphatic endothelial cells. METHODS: Co-culture system of human hepatoma HepG-2 cells and human lymphatic endothelial cells is established by means of transwell chamber; cell growth curve is used to observe the effect of cinobufacini injection on the proliferation of HLEC co-cultured with HepG-2 cells; migration assay is used to observe the effect of cinobufacini injection on the migration of HLEC co-cultured with HepG-2; matrigel assay is used to observe the effect of cinobufacini injection on the tube-like structure formation of HLEC co-cultured with HepG-2 cells. RESULTS: Cinobufacini injection significantly inhibits proliferation(P < 0.05), migration (P < 0.05) and tube-like structure formation (P < 0.05) of HLEC co-cultured with HepG-2 cells in dose dependent ways. CONCLUSION: Cinobufacini injection inhibits proliferation, migration and tube-like structure formation of HLEC co-cultured with HepG-2 cells, which might contribute the inhibiting mechanisms of cinobufacini injection on tumor metastasis.
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Background and purpose:The cinobufacini injection is a traditional antitumor drug.However,its mechanism iS still unclear.The purpose of this study was to observe the effect of cinobufacini injections in DNA TOPO Ⅰ of human hepatocellular carcinoma HcpG-2 cells.Methods:The cells that were proliferated were assessed by MTT assay.Cell cycles were shown through FCM.TOPO Ⅰ mRNA expression was analyzed through RT-PCR.The activity of TOPO Ⅰ was measured by TOPO Ⅰ mediated super coiled PHR322 relaxation.Supercoiled PBR322 was also used to determine the direct DNA breakages.Results:Cinobufacini injections significantly inhibited HepG-2 cells proliferation in ways that were dependent on dosages and time.Induced tumor cells arrest at the S-phase.TOPO ⅠmRNA expression decreased in a manner that was dependent on dosages which inhibited the TOPO Ⅰ mediated DNA relaxations.However,the cinobufacini injections could not directly induce DNA breakage at any concentration.Conclusion:Cinobufacini injections can inhibit human hepatocellular carcinoma HepG-2 cells proliferation.The regulation of topoisomerase Ⅰ activity and mRNA expression may be one of the mechanisms that causes the cinobufacini injection to contribute against tumor.
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Objective: To investigate the effect of cinobufacini on proliferation, celly cycle distribution, invasion capability of MDA-MB-231 breast cancer cell line in vitro and possible mechanism. Methods: The effect of cinobufacini on cell growth was measured by CCK-8 reagent kit. Cell cycle distribution was determined by flow cytometry. The invasion capability in vitro was detected by Transwell chamber assay. The mRNA expressions of cell cycle related factors (cyclin) and p21 were tested by RT-PCR. Results: Cinobufacini inhibited proliferation of MDA-MB-231 cells. The half inhibition concentration (IC50) was 0.31 mg/mL. The inhibitory effect was timE-dependent (P<0.05). Cinobufacini significantly decreased invasion capability of MDA-MB-231 cells in vitro compared with control group (P<0.05). Cinobufacini induced S-phase arrest of MDA-MB-231 cells in a concentration-dependent manner (P<0.000 1). Cinobufacini down-regulated the expression levels of cyclin A1, cyclin D1, and cyclin E1, while up-regulated that of p21 in MDA-MB-231 cell line. However, there was no marked change in the expression of cyclin B1. Conclusion: Cinobufacini inhibits cell proliferation and influences the cell cycle distribution in vitro by regulating the expression of cyclin A1, cyclin D1, cyclin E1 and p21 in breast can-cer cells.
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Objective: To determinate the content of bufalin,resibufogenin and cinobufagin in Cinobufacini Injection. Methods: Liposoluble components in cinobufacini were extracted with ethyl acetate and determined by HPLC using a C 18 column, acetonitrile water(50∶50) as a mobile phase and UV detection wavelength at 299nm. Results: The method showed the good resolution, high sensitivity, satisfactory accuracy and specificity. Quantitatively analyze results showed that the concentration of bufalin, cinobufagin and resibufogenin in Cinobufacini Injection were 0.333 ?g?mL -1 , 0.159?g?mL -1 and 0.110?g?mL -1 , respectively. Conclusion: Bufalin in Cinobufacini Injection reached effective concentration, which was regarded as one of anti cancer components.