| Background:Pancreatic cancer is one of the solid and malignant tumors in human body. So far, how to diagnose and therapy earlier remains difficult all over the world. Currently surgical resection is the main therapeutic approach to deal with pancreatic cancer. But most patients are surgically unresectable at the time of diagnosis. Even in patients with resectable disease, the long-term outcome remains unsatisfactory due to early recurrence after resection. So these years more and more experts consider pancreatic cancer as "the king of cancers in 21th century". Long-term clinical practices have indicated that surgery alone has limited value in the treatment of pancreatic cancer. Currently available chemotherapeutic options for pancreatic cancer are also not very effective mainly due to the emergence of drug resistance. Accordingly, to improve the overall survival of patients with pancreatic cancer, there is an urgent need to develop effective treatment for this disease, such as new chemotherapeutic agents, interventional therapy and gene therapy. The key of improving therapeutic efficacy is toexpand the understanding of etiopathogenesis and molecular/genetic biology of pancreatic cancers, which should facilitate research to develop novel molecular-targeted agents and new herapeutic approachs for this disease.Parthenolide, which is the major sesquiterpene lactone isolated from extracts of Mexican Indian medicinal plants such as feverfew (Tanacetum parthenium), has been used conventionally to treat migraines, rheumatoid arthritis and inflammation for several centuries. Recently it has been reported that parthenolide induces proliferation inhibition and apoptosis of various humen cancer cell lines in vitro, for instance colorectal cancer, hepatoma, cholangiocarcinoma and primary acute/chronic myeloid leukemia. In addition, parthenolide enhances sensitivity of resistant cancer cells to other antitumor agents. Further research has showed that parthenolide -induced apoptosis is associated with inhibition of the antiapoptotic transcription factor nuclear factor-kappa B (NF-κB) activity, mitochondrial dysfunction and the generation of reactive oxygen. However, the detailed mechanism of anticancer effect of parthenolide at the molecular level was not exactly defined. This question, which is the mian purpose of present experiment, attracted our interest.Objectives:The sesquiterpene lactone parthenolide, which is one of the most important active ingredients in the herb European and American, has been used conventionally to treat migraines, rheumatoid arthritis and inflammation for several centuries. Current researches indicate that it may also be one of the effective tumor suppressive agents. Hence, this present study was carried out to investigate the proliferation inhibition and apoptosis induction effect of parthenolide on human pancreatic cancer cells and the possible mechanisms.Methods:The pancreatic cancer BxPC-3 cells were treated with parthenolide at various concentrations in present study. The MTT assay was used to assess cytostatic activity induced by parthenolide. Flow cytometry and DNA fragmentation analysis were adopted to evaluate the cell apoptosis after parthenolide treatment. The wound closure and cell invasion assay were employed to observe the cell migration and invasion ability. Western blotting was used to demonstrate expression levels of involved protein such as Bad, Bcl-2, Bax, caspase-9 and pro-caspase-3.All the detection items in this study were repeated at least 3 times. Statistical analysis was done using SPSS software. The data was expressed as mean ± SD and the statistical significance of the differences between control and parthenolide-treated cells was determined by a two-tailed Student's t test. The Spearman correlation test was used to analyze the correlation between reagents' concentrations and inhibition rates. P-value <0.05 was considered as significant.Results:The MTT assay indicated that the pancreatic cancer cells proliferation could be dose-dependently inhibited by parthenoolide. The EC50 was estimated to be 14.5μM. Flow cytometry showed that parthenolide significantly induced apoptosis in pancreatic tumor BxPC-3 cell line and this phenomenon was confirmed by DNA fragmentation analysis, As the cells displayed disintegrated nuclei and nonrandom DNA fragmentation. The wound closure assay showed that parthenolide significantly suppressed migration ability of pancreatic cancer cells at various concentrations. The cell invasion assay indicated that parthenolide obviously inhiibited invasion ability of pancreatic cancer cells. The cell numbers of 7.5μM and 15μM PTL groups were (94±7)/HPF and (58±8)/HPF, respectively, significant less than (146±10)/HPF ofcontrol group (P<0.05). According to the results of Western Blotting, in contrast to there being no alteration in Bad expression after parthenolide treatment, the Bcl-2 and pro-caspase-3 were down-expressed while the Bax and caspase-9 were up-expressed.Conclusions:In this study, the apoptosis-induced effect of PTL on human pancreatic cancer BxPC-3 cell line was analyzed. The parthenolide can inhibit growth, migration and invasion, also can induce apoptosis of pancreatic cancer cells. The findings presented here reveal that PTL induced marked apoptosis in BxPC-3 cells mainly by influencing several Bcl-2 family members especially the balance of Bcl-2/Bax, which would trigger caspases-induced apoptosis. These data provide preclinical support for chemotherapeutic approach with parthenolide for the treatment of pancreatic cancer. All these results indicate that PTL and similar sesquiterpene lactones may represent a novel class of chemotherapeutic agents for pancreatic cancer.
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