Background The earthworm fibrinolytic enzyme （EFE） is a complex protein enzyme that is widely distributed in the earthworm＇s digestive cavity. Possessing strong protein hydrolysis activity, EFE not only has a direc...Background The earthworm fibrinolytic enzyme （EFE） is a complex protein enzyme that is widely distributed in the earthworm＇s digestive cavity. Possessing strong protein hydrolysis activity, EFE not only has a direct effect on fibrin, but also can activate plasminogen. Its therapeutic and preventative effects on thrombosis-related disease have been confirmed clinically. Recently, there has been increased interest in the anti-tumor activity of EFE. In this study, the anti-tumor activity of EFE, isolated from Eisenia foetida, on human hepatoma cells was evaluated in vitro and in vivo. The potential mechanisms involved were also studied. Methods In vitro experiments were performed in four human hepatoma cell lines： HLE, Huh7, PLC/PRF/5 and HepG2. After treatment with EFE in various concentrations, the inhibition of the rate of cell proliferation was measured. For the in vivo studies, tumor-bearing models xenografted with Huh7 cells were developed in nude mice, and then the mice were fed with EFE once a day for 4 weeks, and the control group received only saline. An inhibitory effect on tumor growth was observed. Also, apoptosis was observed with flow cytometric assay and fluorescent dye staining with acridine orange and ethidium bromide （AO/EB）. The expression of matrix metalloproteinase 2 （MMP-2） were detected by Western blotting assay. Results After treatment with various concentrations of EFE, the proliferation of all hepatoma cell lines was suppressed to varying degrees in vitro. The IC50 for HLE, Huh7, PLC/PCF/5 and HepG2 were 2.11, 5.87, 25.29 and 17.30 uku/ml, respectively. After administration of EFE orally for 4 weeks, the growth of tumor xenograft of Huh7 cells in nude mice was significantly inhibited in vivo. The tumor inhibitory rates in the EFE 500 uku/（kg·d） and 1000 uku/（kg·d） groups were 46.08% （compared with control group, P=0.026） and 57.52% （compared with control group, P=0.002） respectively. Meanwhile, the average weight of body, spleen or thymus did not show any remarkable differences among the various groups. The population in sub-G1 stage was more in the EFE treated groups than in the control group according to flow cytometric assay. After treatment with EFE 0, 5, 10 uku/ml for 72 hours, the apoptotic rates were 3.5%, 10.9% and 12.3% in HLE cells, and 5.0%, 24.7% and 34.5% in Huh7 cells respectively. Under fluorescent staining with AO/EB, the apoptotic morphological changes could be detected more significantly in the EFE treated groups than in the untreated groups. After treatment with EFE in doses of 0, 5, 10 uku/ml for 72 hours, the apoptotic rates were 3.02%, 8.76%, 10.54% in HLE cells, and 3.95%, 18.27%, 30.89% in Huh7 cells respectively. The apoptosis-inducing effects of EFE occurred in a dose dependent manner. Western blotting assay showed that, after treatment with EFE, the secretions of MMP-2 were significantly inhibited in HLE and Huh7 cells. Conclusions EFE showed significant anti-tumor activity in hepatoma cells both in vitro and in vivo, which may be because EFE could induce apoptosis of hepatoma cells and inhibit the expression of MMP-2. This suggests that EFE has a potential role in the treatment of hepatoma.展开更多
Background Chromosomal abnormalities have been shown to play an important prognostic role in multiple myeloma （MM）. Interphase fluorescence in situ hybridization （i-FISH） has been much more effective to identify c...Background Chromosomal abnormalities have been shown to play an important prognostic role in multiple myeloma （MM）. Interphase fluorescence in situ hybridization （i-FISH） has been much more effective to identify cytogenetic aberrations in MM than conventional cytogenetic technique （CC）. To clearly determine the cytogenetic features of Chinese MM patients and identify their prognostic implications, we designed a multicenter study based on i-FISH including 672 patients from 52 hospitals in China. Methods All 672 patients were systematically screened for the following genomic aberrations： del（13q）, IgH rearrangement, del（p53） and lq21 amplifications. Results The analysis showed that the chromosomal changes were detected in 22.1% patients by CC and in 82.3% patients by i-FISH. The most common abnormalities by CC were chromosome 1 aberrations （48.4%）, -13/13q- （37.6%）, hyperdiploidy （36.6%）, hypodiploidy （30.1%） and IgH rearrangements （23.7%）. The most frequent abnormalities by FISH was del（13q）, which was found in 60.4% patients, whereas IgH rearrangement, lq21 amplification and p53 deletions were detected in 57.6%, 49.0% and 34.7% cases, respectively. By statistical analysis, -13/13q- by CC was associated with low level of platelet （P=0.015）, hyperdiploidy was associated with low level of serum albumin （P=0.028）, and IgH rearrangement by FISH was associated with high level of 132 microglobulin （P=0.019）. Moreover, lq21 amplification and del（p53） by FISH conferred a high incidence of progressive disease （PD） after initial therapy. Metaphase detection of IgH rearrangements and chromosome 1 aberrations concurrently was associated with a short progression free survival （PFS） （P=-0.036）. No significant prognostic implications of other cytogenetic abnormalities were found associated with overall survival and PFS. Conclusions Chinese MM patients had similar cytogenetic abnormalities compared with the previous reported studies. However, the prognostic significance of FISH aberrations were not clearly determined and further study is required.展开更多
Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel ...Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel anticancer drugs with multidrug-resistance modulating potential to increase the survival rate of leukemia patients. Plant-derived natural products have been used for the treatment of various diseases for thousands of years. This review summarizes the anticancer and multidrug-resistance reversing properties of the extracts and bioactive compounds from traditional medicinal plants in different leukemia cell lines. Further mechanistic studies will pave the road to establish the anticancer potential of plant-derived natural compounds.展开更多
Garcinia, a kind of dry resin secreted by Garcinia hanburyi Hook. F. G., is a traditional Chinese medicine with various biological functions such as detoxification, anti-inflammatory, and anthelmintic activities. Rece...Garcinia, a kind of dry resin secreted by Garcinia hanburyi Hook. F. G., is a traditional Chinese medicine with various biological functions such as detoxification, anti-inflammatory, and anthelmintic activities. Recent studies suggest that garcinia has potential anticancer activity. Increasing evidences indicate that the main active monomer gambogic acid isolated from garcinia can inhibit the growth of various cancer cells. Neogambogic acid is an isolated compound with a similar chemical structure as gambogic acid. Preliminary studies show that the neogambogic acid can selectively inhibit the growth of various cancer cells, and has a broader antitumor activity and lower toxicity than gambogic acid. In this review, we summarize the advances made in the investigation of the anti-tumor effect of neogambogic acid in recent years.展开更多
Multidrug resistance(MDR) in human cancer is one of greatest challenges in cancer therapy.Natural products,especially the alkaloids,exert reversed effects on MDR with low toxicity,by interacting with various targets.I...Multidrug resistance(MDR) in human cancer is one of greatest challenges in cancer therapy.Natural products,especially the alkaloids,exert reversed effects on MDR with low toxicity,by interacting with various targets.In this review article,we summarize the recent progress made in the research of the main alkaloids,including classification,function,mechanism,research status,and application in reversing MDR.展开更多
Background Dihydropyrimidine dehydrogenase （DPD）, a key enzyme involved in the catabolism of 5-fluorouracil （5-FU）, is the attractive candidate for pharmacogenetic research on efficacies and toxicities of 5-FU. Th...Background Dihydropyrimidine dehydrogenase （DPD）, a key enzyme involved in the catabolism of 5-fluorouracil （5-FU）, is the attractive candidate for pharmacogenetic research on efficacies and toxicities of 5-FU. The aim of this study is to explore the association between polymorphisms of dihydropyrimidine dehydrogenase gene （DPYD） and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in the Chinese population.展开更多
Background Platinum-based chemotherapeutics are the most common regimens for advanced non-small-cell lung cancer （NSCLC） patients, and genetic factors are thought to represent important determinants of drug efficacy...Background Platinum-based chemotherapeutics are the most common regimens for advanced non-small-cell lung cancer （NSCLC） patients, and genetic factors are thought to represent important determinants of drug efficacy. We prospectively assessed the status of the XPC Ala499Val and Lys939GIn gene polymorphisms and investigated whether these SNPs can predict the response to cisplatin/carboplatin-based regimens in advanced NSCLC patients in a Chinese population.Methods The treatment outcomes of 96 advanced NSCLC patients who were treated with platinum-based chemotherapy were evaluated. The polymorphic status of xeroderma pigmentosum group C （XPC） gene was genotyped by the 3-D polyacrylamide gel-based DNA microarray method.Results The distributions of XPC Lys939GIn genotypes differed significantly between the response group （complete ＋partial responses） and the non-response group （stable ＋ progressive disease; P=0.022）. The heterozygous A/C genotype carriers had a poorer response rate than the wild A/A genotype carriers in stage Ⅲ （OR, 0.074; 95% CI,0.008-0.704; P=0.023）. The XPC Ala499Val polymorphisms were not associated with response to platinum-based chemotherapy.Conclusion Polymorphisms of the XPC gene, Lys939GIn, may be a predictive marker of treatment response for advanced NSCLC patients in stage Ⅲ.展开更多
As the chemotherapeutic resistance of extranodal NK/T-cell lymphoma(ENKTL) rises year by year, searching for novel chemoprevention compounds has become imminent. Gambogic acid(GA) has recently been shown to have anti-...As the chemotherapeutic resistance of extranodal NK/T-cell lymphoma(ENKTL) rises year by year, searching for novel chemoprevention compounds has become imminent. Gambogic acid(GA) has recently been shown to have anti-tumor effects, but its role and underling mechanism in ENKTL are rather elusive. In the present study, we showed that GA inhibited the cell growth and potently induced the apoptosis of ENKTL cells in vitro in a time-and concentration-dependent manner. Furthermore, GA induced cell death through endoplasmic reticulum stress(ERS) mediated suppression of Akt signaling pathways and finally the release of the caspase-3 proteases. Overall, our data provided evidences supporting GA as a potential therapeutic agent for ENKTL, which may facilitate further preclinical development of anti-tumor drugs.展开更多
Background The cytosine arabinoside （Ara-C）-based chemotherapy is the major remedial measure for acute myeloid leukemia （AML）. Deoxycytidine kinase （DCK） and cytidine deaminase （CDA） are the key enzymes in the...Background The cytosine arabinoside （Ara-C）-based chemotherapy is the major remedial measure for acute myeloid leukemia （AML）. Deoxycytidine kinase （DCK） and cytidine deaminase （CDA） are the key enzymes in the metabolism of Ara-C. Many single nucleotide polymorphisms （SNPs） and haplotypes of DCK and CDA, which contribute to susceptibility to Ara-C, have been identified in Africans and Europeans. However, there has been no report about the relation among three SNPs in DCK （rs115543896, rs72552079, and rs111454937） and two SNPs in CDA （rs2072671 and rs60369023）, and their clinical response to Ara-C for a Chinese population. In this study, we aimed to investigate whether these five SNPs are associated with the therapeutic outcomes of Ara-C-based chemotherapy regimens in patients with AML. Methods A total of 151 Chinese patients with AML were enrolled in our study. SNPs genotyping were performed using the MassARRAY system by means of the matrix-assisted laser desorption ionization-time of flight mass spectrometry （MALDI-TOF-MS） method. Results The results illustrated that DCKrs111454937 AA genotype was more frequent in patients with higher platelet count, and A allele frequency was significantly higher in the group 〈40 years, lower white blood cell （WBC） count patients group and the group with platelet counts 〉60xl0e/L. Meanwhile, both DCKrs72552079 TC （OR=1.225, 95% C1=1.225-9.851, P=0.0192） and CDArs60369023 GA （OR=9.851,95% C1=1.31-77.93, ,~=-0.0263） significantly improved Ara-C-based chemotherapy response. While DCKrs11554389 AA （OR=0.147, 95% CI=0.027-0.801, P=0.0267） was associated with the decrease of Ara-C-based chemotherapy response. Conclusion It is evident that the DCK and CDA polymorphisms might be the important markers for the AML patients＇ therapy outcomes in a Chinese population.展开更多
文摘Background The earthworm fibrinolytic enzyme （EFE） is a complex protein enzyme that is widely distributed in the earthworm＇s digestive cavity. Possessing strong protein hydrolysis activity, EFE not only has a direct effect on fibrin, but also can activate plasminogen. Its therapeutic and preventative effects on thrombosis-related disease have been confirmed clinically. Recently, there has been increased interest in the anti-tumor activity of EFE. In this study, the anti-tumor activity of EFE, isolated from Eisenia foetida, on human hepatoma cells was evaluated in vitro and in vivo. The potential mechanisms involved were also studied. Methods In vitro experiments were performed in four human hepatoma cell lines： HLE, Huh7, PLC/PRF/5 and HepG2. After treatment with EFE in various concentrations, the inhibition of the rate of cell proliferation was measured. For the in vivo studies, tumor-bearing models xenografted with Huh7 cells were developed in nude mice, and then the mice were fed with EFE once a day for 4 weeks, and the control group received only saline. An inhibitory effect on tumor growth was observed. Also, apoptosis was observed with flow cytometric assay and fluorescent dye staining with acridine orange and ethidium bromide （AO/EB）. The expression of matrix metalloproteinase 2 （MMP-2） were detected by Western blotting assay. Results After treatment with various concentrations of EFE, the proliferation of all hepatoma cell lines was suppressed to varying degrees in vitro. The IC50 for HLE, Huh7, PLC/PCF/5 and HepG2 were 2.11, 5.87, 25.29 and 17.30 uku/ml, respectively. After administration of EFE orally for 4 weeks, the growth of tumor xenograft of Huh7 cells in nude mice was significantly inhibited in vivo. The tumor inhibitory rates in the EFE 500 uku/（kg·d） and 1000 uku/（kg·d） groups were 46.08% （compared with control group, P=0.026） and 57.52% （compared with control group, P=0.002） respectively. Meanwhile, the average weight of body, spleen or thymus did not show any remarkable differences among the various groups. The population in sub-G1 stage was more in the EFE treated groups than in the control group according to flow cytometric assay. After treatment with EFE 0, 5, 10 uku/ml for 72 hours, the apoptotic rates were 3.5%, 10.9% and 12.3% in HLE cells, and 5.0%, 24.7% and 34.5% in Huh7 cells respectively. Under fluorescent staining with AO/EB, the apoptotic morphological changes could be detected more significantly in the EFE treated groups than in the untreated groups. After treatment with EFE in doses of 0, 5, 10 uku/ml for 72 hours, the apoptotic rates were 3.02%, 8.76%, 10.54% in HLE cells, and 3.95%, 18.27%, 30.89% in Huh7 cells respectively. The apoptosis-inducing effects of EFE occurred in a dose dependent manner. Western blotting assay showed that, after treatment with EFE, the secretions of MMP-2 were significantly inhibited in HLE and Huh7 cells. Conclusions EFE showed significant anti-tumor activity in hepatoma cells both in vitro and in vivo, which may be because EFE could induce apoptosis of hepatoma cells and inhibit the expression of MMP-2. This suggests that EFE has a potential role in the treatment of hepatoma.
文摘Background Chromosomal abnormalities have been shown to play an important prognostic role in multiple myeloma （MM）. Interphase fluorescence in situ hybridization （i-FISH） has been much more effective to identify cytogenetic aberrations in MM than conventional cytogenetic technique （CC）. To clearly determine the cytogenetic features of Chinese MM patients and identify their prognostic implications, we designed a multicenter study based on i-FISH including 672 patients from 52 hospitals in China. Methods All 672 patients were systematically screened for the following genomic aberrations： del（13q）, IgH rearrangement, del（p53） and lq21 amplifications. Results The analysis showed that the chromosomal changes were detected in 22.1% patients by CC and in 82.3% patients by i-FISH. The most common abnormalities by CC were chromosome 1 aberrations （48.4%）, -13/13q- （37.6%）, hyperdiploidy （36.6%）, hypodiploidy （30.1%） and IgH rearrangements （23.7%）. The most frequent abnormalities by FISH was del（13q）, which was found in 60.4% patients, whereas IgH rearrangement, lq21 amplification and p53 deletions were detected in 57.6%, 49.0% and 34.7% cases, respectively. By statistical analysis, -13/13q- by CC was associated with low level of platelet （P=0.015）, hyperdiploidy was associated with low level of serum albumin （P=0.028）, and IgH rearrangement by FISH was associated with high level of 132 microglobulin （P=0.019）. Moreover, lq21 amplification and del（p53） by FISH conferred a high incidence of progressive disease （PD） after initial therapy. Metaphase detection of IgH rearrangements and chromosome 1 aberrations concurrently was associated with a short progression free survival （PFS） （P=-0.036）. No significant prognostic implications of other cytogenetic abnormalities were found associated with overall survival and PFS. Conclusions Chinese MM patients had similar cytogenetic abnormalities compared with the previous reported studies. However, the prognostic significance of FISH aberrations were not clearly determined and further study is required.
基金supported by the National Natural Science Foundation of P.R.China(Nos.81170492,81370673)National High Technology Research and Development Program 863 of P.R.China(No.2012AA022703)+2 种基金National Key Basic Research Program 973 of P.R.China(No.2010CB732404)Key Medical Projects of Jiangsu Province(No.BL2014078)Key Discipline of Jiangsu Province(2011-2015)
文摘Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel anticancer drugs with multidrug-resistance modulating potential to increase the survival rate of leukemia patients. Plant-derived natural products have been used for the treatment of various diseases for thousands of years. This review summarizes the anticancer and multidrug-resistance reversing properties of the extracts and bioactive compounds from traditional medicinal plants in different leukemia cell lines. Further mechanistic studies will pave the road to establish the anticancer potential of plant-derived natural compounds.
基金supported by the Fundamental Research Funds for the Central Universities(No.KYLX15-0186)the Key Medical Projects of Jiangsu Province(No.BL2014078)the Key Discipline of Jiangsu Province(No.2016-2020)
文摘Garcinia, a kind of dry resin secreted by Garcinia hanburyi Hook. F. G., is a traditional Chinese medicine with various biological functions such as detoxification, anti-inflammatory, and anthelmintic activities. Recent studies suggest that garcinia has potential anticancer activity. Increasing evidences indicate that the main active monomer gambogic acid isolated from garcinia can inhibit the growth of various cancer cells. Neogambogic acid is an isolated compound with a similar chemical structure as gambogic acid. Preliminary studies show that the neogambogic acid can selectively inhibit the growth of various cancer cells, and has a broader antitumor activity and lower toxicity than gambogic acid. In this review, we summarize the advances made in the investigation of the anti-tumor effect of neogambogic acid in recent years.
基金supported by the National Natural Science Foundation of China(Nos.81170492 and 81370673)the Key Medical Subjects of Jiangsu Province,China(No.BL2014078)the Key Department of Jiangsu Province,China(2016-2020)
文摘Multidrug resistance(MDR) in human cancer is one of greatest challenges in cancer therapy.Natural products,especially the alkaloids,exert reversed effects on MDR with low toxicity,by interacting with various targets.In this review article,we summarize the recent progress made in the research of the main alkaloids,including classification,function,mechanism,research status,and application in reversing MDR.
文摘Background Dihydropyrimidine dehydrogenase （DPD）, a key enzyme involved in the catabolism of 5-fluorouracil （5-FU）, is the attractive candidate for pharmacogenetic research on efficacies and toxicities of 5-FU. The aim of this study is to explore the association between polymorphisms of dihydropyrimidine dehydrogenase gene （DPYD） and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in the Chinese population.
基金This work was supported by the grants from the Prophase Force-Study Program of the Jiangsu Province Natural Science Foundation （No. BK2005203）, the Medical Science Technology Research ＂Eleventh Five-Year＂ Program of the People＇s Liberation Army （No. 06MAlll）, and the Focal Project of Nanjing Medical Technology Development （No. ZKX05030）.
文摘Background Platinum-based chemotherapeutics are the most common regimens for advanced non-small-cell lung cancer （NSCLC） patients, and genetic factors are thought to represent important determinants of drug efficacy. We prospectively assessed the status of the XPC Ala499Val and Lys939GIn gene polymorphisms and investigated whether these SNPs can predict the response to cisplatin/carboplatin-based regimens in advanced NSCLC patients in a Chinese population.Methods The treatment outcomes of 96 advanced NSCLC patients who were treated with platinum-based chemotherapy were evaluated. The polymorphic status of xeroderma pigmentosum group C （XPC） gene was genotyped by the 3-D polyacrylamide gel-based DNA microarray method.Results The distributions of XPC Lys939GIn genotypes differed significantly between the response group （complete ＋partial responses） and the non-response group （stable ＋ progressive disease; P=0.022）. The heterozygous A/C genotype carriers had a poorer response rate than the wild A/A genotype carriers in stage Ⅲ （OR, 0.074; 95% CI,0.008-0.704; P=0.023）. The XPC Ala499Val polymorphisms were not associated with response to platinum-based chemotherapy.Conclusion Polymorphisms of the XPC gene, Lys939GIn, may be a predictive marker of treatment response for advanced NSCLC patients in stage Ⅲ.
基金supported by the National Natural Science Foundation of China(Nos.81502588 and 81370673)Agency of Jiangsu Province Science and Technology(Nos.2013035 and BK20151018)+2 种基金the Key Medical subjects of Jiangsu Province(No.BL2014078)Research Office of Jiangsu Cancer Hospital(No.ZK201401)the Key Discipline of Jiangsu Province(2016-2020)
文摘As the chemotherapeutic resistance of extranodal NK/T-cell lymphoma(ENKTL) rises year by year, searching for novel chemoprevention compounds has become imminent. Gambogic acid(GA) has recently been shown to have anti-tumor effects, but its role and underling mechanism in ENKTL are rather elusive. In the present study, we showed that GA inhibited the cell growth and potently induced the apoptosis of ENKTL cells in vitro in a time-and concentration-dependent manner. Furthermore, GA induced cell death through endoplasmic reticulum stress(ERS) mediated suppression of Akt signaling pathways and finally the release of the caspase-3 proteases. Overall, our data provided evidences supporting GA as a potential therapeutic agent for ENKTL, which may facilitate further preclinical development of anti-tumor drugs.
文摘Background The cytosine arabinoside （Ara-C）-based chemotherapy is the major remedial measure for acute myeloid leukemia （AML）. Deoxycytidine kinase （DCK） and cytidine deaminase （CDA） are the key enzymes in the metabolism of Ara-C. Many single nucleotide polymorphisms （SNPs） and haplotypes of DCK and CDA, which contribute to susceptibility to Ara-C, have been identified in Africans and Europeans. However, there has been no report about the relation among three SNPs in DCK （rs115543896, rs72552079, and rs111454937） and two SNPs in CDA （rs2072671 and rs60369023）, and their clinical response to Ara-C for a Chinese population. In this study, we aimed to investigate whether these five SNPs are associated with the therapeutic outcomes of Ara-C-based chemotherapy regimens in patients with AML. Methods A total of 151 Chinese patients with AML were enrolled in our study. SNPs genotyping were performed using the MassARRAY system by means of the matrix-assisted laser desorption ionization-time of flight mass spectrometry （MALDI-TOF-MS） method. Results The results illustrated that DCKrs111454937 AA genotype was more frequent in patients with higher platelet count, and A allele frequency was significantly higher in the group 〈40 years, lower white blood cell （WBC） count patients group and the group with platelet counts 〉60xl0e/L. Meanwhile, both DCKrs72552079 TC （OR=1.225, 95% C1=1.225-9.851, P=0.0192） and CDArs60369023 GA （OR=9.851,95% C1=1.31-77.93, ,~=-0.0263） significantly improved Ara-C-based chemotherapy response. While DCKrs11554389 AA （OR=0.147, 95% CI=0.027-0.801, P=0.0267） was associated with the decrease of Ara-C-based chemotherapy response. Conclusion It is evident that the DCK and CDA polymorphisms might be the important markers for the AML patients＇ therapy outcomes in a Chinese population.
