Background Small cell lung cancer （SCLC） is the most aggressive form of lung cancer. This study aimed to investigate the mechanism of human small cell lung cancer cell line resistance to etoposide （VP-16）, H446NP....Background Small cell lung cancer （SCLC） is the most aggressive form of lung cancer. This study aimed to investigate the mechanism of human small cell lung cancer cell line resistance to etoposide （VP-16）, H446NP. Methods The cell viability was measured by MTT assay. Immunocytochemistry, reverse transcription-polymerase chain reaction （RT-PCR） and Western blotting methods were used to detect the multidrug resistance gene （MDR1）, bcl-2, bax and the topoisomerase Ⅱ （TopoⅡ） expressions in H446 and H446NP cells after treated with or without VP-16. Results The 50% inhibition concentration （IC50） of VP-16 on H446 cells was 49 mg/L, and 836 mg/L was for H446NP cells. The expressions of MDR1 and bcl-2 were up-regulated, while the amounts of bax and Topo II were reduced in H446NP cells. After treated with 49 mg/L of VP-16, it showed that the drug could significantly inhibit bcl-2 and Topo fl expressions, and increase bax expression in H446 cells compared with that of H446NP cells. Conclusions The H446NP cell was stably resistant to VP-16. The decreased expression of Topo II was correlated with the H446NP multidrug resistance. The elevated expressions of MDR1, and the altered apoptotic pathways also played an important role in VP-16 induced multidrug resistance of SCLC.展开更多
Cancer is a leading cause of death globally, claiming about 9.6 million lives and approximately 420 million new cases of cancer will be diagnosed in the world by the year 2025. The aim of this study was to synthesize ...Cancer is a leading cause of death globally, claiming about 9.6 million lives and approximately 420 million new cases of cancer will be diagnosed in the world by the year 2025. The aim of this study was to synthesize and computationally evaluate pharmacological potential of some derivatives of 9-amino-3-phenylacridone, as topoisomerase II (Topo II) inhibitors. In this study, 10 derivatives of 3-phenyl-9-aminoacridone were chemically synthesized and characterized, and the potential pharmacological indications of these compounds were computationally predicted by methods such as ADMET prediction, molecular target prediction and molecular docking. The results showed that two derivatives (58e and 58j) were non-permeant of blood-brain barrier, and this property was found similar to that of amsacrine and etoposide. The results of molecular docking of the ten derivatives of 3-phenyl-9-aminoacridone that were synthesized in this work showed that the synthetic compounds (58a-j) and the standard drugs have overall best binding affinities for human acetylcholine esterase than butyrylcholinesterase, and overall best binding affinities for human topo IIα than human topo IIβ. Overall, the results of this study suggest that the synthetic compounds 58a, 58c, 58f, 58g, and 58i could probably inhibit topo IIα by catalytic inhibition as seen with amsacrine, but only 58b and 58e possessed DNA non-intercalation properties as seen with etoposide, serving as topo II poison. In conclusion, this study showed that 3-phenyl-9-aminoacridone derivatives are potential inhibitor of topo IIα/β both by catalytic inhibition and poison as non-intercalator of DNA.展开更多
OBJECTIVE Lapachol is a natural naphthoquinone compound that possesses extensive biological activities.The aim of this study is to investigate the inhibitory effects of lapachol on rat C6 glioma both in vitro and in v...OBJECTIVE Lapachol is a natural naphthoquinone compound that possesses extensive biological activities.The aim of this study is to investigate the inhibitory effects of lapachol on rat C6 glioma both in vitro and in vivo,as well as the potential mechanisms.METHODS The antitumor effect of lapachol was firstly evaluated in the C6 glioma model in Wistar rats.The effects of lapachol on C6 cell proliferation,apoptosis and DNA damage were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium(MTS)/phenazinemethosulfate(PMS)assay,hoechst 33358 staining,annexinⅤ-FITC/PI staining,and comet assay.Effects of lapachol on topoisomerase I(TOP I)and topoisomeraseⅡ(TOPⅡ)activities were detected by TOPⅠand TOPⅡmediated supercoiled p BR322DNA relaxation assays and molecular docking.TOPⅠand TOPⅡexpression levels in C6 cells were also determined.RESULTS High dose lapachol showed significant inhibitory effect on the C6 glioma in Wistar rats(P<0.05).It was showed that lapachol could inhibit proliferation,induce apoptosis and DNA damage of C6 cel s in dose dependent manners.Lapachol could inhibit the activities of both TOPⅠ and Ⅱ.Lapachol-TOPⅠshowed relatively stronger interaction than that of lapachol-TOPⅡin molecular docking study.Also,lapachol could inhibit TOPⅡexpression levels,but not TOPⅠexpression levels.CONCLUSION These results showed that lapachol could significantly inhibit C6 glioma both in vivo and in vitro,which might be related with inhibiting TOPⅠ and TOPⅡ activities,as wel as TOPⅡ expression.展开更多
Background Surrogate markers may be used to assess the response to neoadjuvant treatment. The association between HER2 overexpression and favorable response to specific therapy in breast cancer is controversial, and t...Background Surrogate markers may be used to assess the response to neoadjuvant treatment. The association between HER2 overexpression and favorable response to specific therapy in breast cancer is controversial, and the mechanism unclear. The purpose of the study was to evaluate HER2 and topoisomerase Ⅱα （Topo Ⅱα） as candidates for predicting the response to neoadjuvant chemotherapy in breast cancer patients.Methods Between 1999 and 2006, seventy-six breast cancer patients who had received neoadjuvant chemotherapy were studied. Regimens including either CEF （cyclophosphamide, epirubicin, 5-fluorouracil） or CMF （cyclophosphamide, methotrexate, 5-fluorouracil） were given in more than three cycles to this group of patients. Protein expression of HER2 and Topo Ⅱα were determined by immunohistochemistry. The primary endpoint was pathological and clinical response.Results Of 76 primary breast cancer samples, 27 （35.5%） showed overexpression of either HER2 （25%） or Topo Ⅱα protein （10.5%）, whereas in 7 tumors （9.2%） both proteins were found to be overexpressed. Ten patients （13.2%） had a clinical complete response and 21 （27.6%） had a clinical partial response. Five women （6.6%） had a pathological complete response, 5 （6.6%） had microscopic residual disease, and 46 （60.5%） had macroscopic residual disease. HER2 and Topo Ⅱα overexpression was significantly associated with a favorable response （P 〈0.001 and P=0.005 respectively）.Conclusion Our study suggests that HER2 and Topo Ⅱα overexpression could be predictors of the response to neoadjuvant chemothrapy in both the CEF and CMF arms.展开更多
文摘Background Small cell lung cancer （SCLC） is the most aggressive form of lung cancer. This study aimed to investigate the mechanism of human small cell lung cancer cell line resistance to etoposide （VP-16）, H446NP. Methods The cell viability was measured by MTT assay. Immunocytochemistry, reverse transcription-polymerase chain reaction （RT-PCR） and Western blotting methods were used to detect the multidrug resistance gene （MDR1）, bcl-2, bax and the topoisomerase Ⅱ （TopoⅡ） expressions in H446 and H446NP cells after treated with or without VP-16. Results The 50% inhibition concentration （IC50） of VP-16 on H446 cells was 49 mg/L, and 836 mg/L was for H446NP cells. The expressions of MDR1 and bcl-2 were up-regulated, while the amounts of bax and Topo II were reduced in H446NP cells. After treated with 49 mg/L of VP-16, it showed that the drug could significantly inhibit bcl-2 and Topo fl expressions, and increase bax expression in H446 cells compared with that of H446NP cells. Conclusions The H446NP cell was stably resistant to VP-16. The decreased expression of Topo II was correlated with the H446NP multidrug resistance. The elevated expressions of MDR1, and the altered apoptotic pathways also played an important role in VP-16 induced multidrug resistance of SCLC.
文摘Cancer is a leading cause of death globally, claiming about 9.6 million lives and approximately 420 million new cases of cancer will be diagnosed in the world by the year 2025. The aim of this study was to synthesize and computationally evaluate pharmacological potential of some derivatives of 9-amino-3-phenylacridone, as topoisomerase II (Topo II) inhibitors. In this study, 10 derivatives of 3-phenyl-9-aminoacridone were chemically synthesized and characterized, and the potential pharmacological indications of these compounds were computationally predicted by methods such as ADMET prediction, molecular target prediction and molecular docking. The results showed that two derivatives (58e and 58j) were non-permeant of blood-brain barrier, and this property was found similar to that of amsacrine and etoposide. The results of molecular docking of the ten derivatives of 3-phenyl-9-aminoacridone that were synthesized in this work showed that the synthetic compounds (58a-j) and the standard drugs have overall best binding affinities for human acetylcholine esterase than butyrylcholinesterase, and overall best binding affinities for human topo IIα than human topo IIβ. Overall, the results of this study suggest that the synthetic compounds 58a, 58c, 58f, 58g, and 58i could probably inhibit topo IIα by catalytic inhibition as seen with amsacrine, but only 58b and 58e possessed DNA non-intercalation properties as seen with etoposide, serving as topo II poison. In conclusion, this study showed that 3-phenyl-9-aminoacridone derivatives are potential inhibitor of topo IIα/β both by catalytic inhibition and poison as non-intercalator of DNA.
文摘OBJECTIVE Lapachol is a natural naphthoquinone compound that possesses extensive biological activities.The aim of this study is to investigate the inhibitory effects of lapachol on rat C6 glioma both in vitro and in vivo,as well as the potential mechanisms.METHODS The antitumor effect of lapachol was firstly evaluated in the C6 glioma model in Wistar rats.The effects of lapachol on C6 cell proliferation,apoptosis and DNA damage were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium(MTS)/phenazinemethosulfate(PMS)assay,hoechst 33358 staining,annexinⅤ-FITC/PI staining,and comet assay.Effects of lapachol on topoisomerase I(TOP I)and topoisomeraseⅡ(TOPⅡ)activities were detected by TOPⅠand TOPⅡmediated supercoiled p BR322DNA relaxation assays and molecular docking.TOPⅠand TOPⅡexpression levels in C6 cells were also determined.RESULTS High dose lapachol showed significant inhibitory effect on the C6 glioma in Wistar rats(P<0.05).It was showed that lapachol could inhibit proliferation,induce apoptosis and DNA damage of C6 cel s in dose dependent manners.Lapachol could inhibit the activities of both TOPⅠ and Ⅱ.Lapachol-TOPⅠshowed relatively stronger interaction than that of lapachol-TOPⅡin molecular docking study.Also,lapachol could inhibit TOPⅡexpression levels,but not TOPⅠexpression levels.CONCLUSION These results showed that lapachol could significantly inhibit C6 glioma both in vivo and in vitro,which might be related with inhibiting TOPⅠ and TOPⅡ activities,as wel as TOPⅡ expression.
基金The National Natural Science Foundation(No.20637030)The National Science and Technology Surporting Item(No.2006BAJ08B01-02)The Science and Technology Department of Jiangsu Province of The People’s Republic of China(No.BS2007160)
文摘Background Surrogate markers may be used to assess the response to neoadjuvant treatment. The association between HER2 overexpression and favorable response to specific therapy in breast cancer is controversial, and the mechanism unclear. The purpose of the study was to evaluate HER2 and topoisomerase Ⅱα （Topo Ⅱα） as candidates for predicting the response to neoadjuvant chemotherapy in breast cancer patients.Methods Between 1999 and 2006, seventy-six breast cancer patients who had received neoadjuvant chemotherapy were studied. Regimens including either CEF （cyclophosphamide, epirubicin, 5-fluorouracil） or CMF （cyclophosphamide, methotrexate, 5-fluorouracil） were given in more than three cycles to this group of patients. Protein expression of HER2 and Topo Ⅱα were determined by immunohistochemistry. The primary endpoint was pathological and clinical response.Results Of 76 primary breast cancer samples, 27 （35.5%） showed overexpression of either HER2 （25%） or Topo Ⅱα protein （10.5%）, whereas in 7 tumors （9.2%） both proteins were found to be overexpressed. Ten patients （13.2%） had a clinical complete response and 21 （27.6%） had a clinical partial response. Five women （6.6%） had a pathological complete response, 5 （6.6%） had microscopic residual disease, and 46 （60.5%） had macroscopic residual disease. HER2 and Topo Ⅱα overexpression was significantly associated with a favorable response （P 〈0.001 and P=0.005 respectively）.Conclusion Our study suggests that HER2 and Topo Ⅱα overexpression could be predictors of the response to neoadjuvant chemothrapy in both the CEF and CMF arms.
