Elemene Antitumor Drugs Development Based on "Molecular Compatibility Theory" and Clinical Application: A Retrospective and Prospective Outlook / 中国结合医学杂志

Elemene, derived from Curcuma wenyujin, one of the "8 famous genuine medicinal materials of Zhejiang province," exhibits remarkable antitumor activity. It has gained wide recognition in clinical practice for effectiveness on tumors. Dr. XIE Tian, introduced the innovative concept of "molecular compatibility theory" by combining Chinese medicine principles, specifically the "monarch, minister, assistant, and envoy" theory, with modern biomedical technology. This groundbreaking approach, along with a systematic analysis of Chinese medicine and modern biomedical knowledge, led to the development of elemene nanoliposome formulations. These novel formulations offer numerous advantages, including low toxicity, well-defined composition, synergistic effects on multiple targets, and excellent biocompatibility. Following the principles of the "molecular compatibility theory", further exploration of cancer treatment strategies and methods based on elemene was undertaken. This comprehensive review consolidates the current understanding of elemene's potential antitumor mechanisms, recent clinical investigations, advancements in drug delivery systems, and structural modifications. The ultimate goal of this review is to establish a solid theoretical foundation for researchers, empowering them to develop more effective antitumor drugs based on the principles of "molecular compatibility theory".

Exploring the mechanism of elemene synergistic bortezomib against multiple myeloma by ROS-NF-κB-p38MAPK pathway / 中国临床药理学与治疗学

AIM: To investigate the mechanism of elemene synergistic bortezomib against multiple myeloma based on ROS-NF-κB-p38MAPK signaling pathway. METHODS: CCK-8 assay was used to detect cell activity. Nude mice were randomly divided into control group, bortezomib (BTZ) group, elemene (ELE) group and combination group. Each group was treated with BTZ, ELE and BTZ combined with ELE, respectively. Tunel staining was performed to observe the apoptosis of tumor tissues. The expressions of Caspase-3, Bcl-2, NF-κB and p38 MAPK were detected by Western Blot. Cell cycle, apoptosis and reactive oxygen species (ROS) expression were detected by flow cytometry using human myeloma U266 cells. RESULTS: When 4.0 μmol/L ELE combined with 50 nmol/L BTZ treated U266, the cell activity was significantly reduced compared with that of NC, BTZ and ELE groups (P< 0.05). The tumor volume of nude mice in BTZ group, ELE group and combined group was significantly reduced compared with the control group (P <0.05), and the combined group was the smallest. Tunel staining results showed that the apoptosis level in the control group was lower than that in the BTZ group, ELE group and the combined group (P<0.05), and the combined group had the lowest apoptosis level. Compared with the control group, the expressions of Caspase-3 and p38 MAPK in BTZ group, ELE group and combination group were significantly increased, while the expression of Bcl-2 was significantly decreased. The apoptosis level and expression of ROS in BTZ group, ELE group and the combined group was significantly increased compared with the control group (P<0.05). CONCLUSION: ELE can enhance the role of BTZ in promoting apoptosis of myeloma cells, which may be achieved by regulating ROS/NF-κB/p38 MAPK signaling pathway to enhance the level of apoptosis of tumor cells to achieve anti-tumor effect.

Discovery and bioassay of disubstituted β-elemene-NO donor conjugates: synergistic enhancement in the treatment of leukemia / 中国天然药物

Natural products are essential sources of antitumor drugs. One such molecule, β-elemene, is a potent antitumor compound extracted from Curcuma wenyujin. In the present investigation, a series of novel 13,14-disubstituted nitric oxide (NO)-donor β-elemene derivatives were designed, with β-elemene as the foundational compound, and subsequently synthesized to evaluate their therapeutic potential against leukemia. Notably, the derivative labeled as compound 13d demonstrated a potent anti-proliferative activity against the K562 cell line, with a high NO release. In vivo studies indicated that compound 13d could effectively inhibit tumor growth, exhibiting no discernible toxic manifestations. Specifically, a significant tumor growth inhibition rate of 62.9% was observed in the K562 xenograft tumor mouse model. The accumulated data propound the potential therapeutic application of compound 13d in the management of leukemia.

β-Elemene induces apoptosis and autophagy in colorectal cancer cells through regulating the ROS/AMPK/mTOR pathway / 中国天然药物

β-Elemene is an effective anti-cancer ingredient extracted from the genus Curcuma (Zingiberaceae familiy). In the present study, we demonstrated that β-elemene inhibited the proliferation of colorectal cancer cells and induced cell cycle arrest in the G2/M phase. In addition, β-elemene induced nuclear chromatin condensation and cell membrane phosphatidylserine eversion, decreased cell mitochondrial membrane potential, and promoted the cleavage of caspase-3, caspase-9 and PARP proteins, indicating apoptosis in colorectal cancer cells. At the same time, β-elemene induced autophagy response, and the treated cells showed autophagic vesicle bilayer membrane structure, which was accompanied by up-regulation of the expression of LC3B and SQSTM1. Furthermore, β-elemene increased ROS levels in colorectal cancer cells, promoted phosphorylation of AMPK protein, and inhibited mTOR protein phosphorylation. In the experiments in vivo, β-elemene inhibited the tumor size and induced apoptosis and autophagy in nude mice. In summary, β-elemene inhibited the occurrence and development of colon cancer xenografts in nude mice, and significantly induced apoptosis and autophagy in colorectal cancer cells in vitro. These effects were associated with regulation of the ROS/AMPK/mTOR signaling. We offered a molecular basis for the development of β-elemene as a promising anti-tumor drug candidate for colorectal cancer.

Research on Biosynthesis of Anticancer Drug Elemene and Key Enzyme Germacrane A Synthase / 中国生物化学与分子生物学报

Elemene is one of the anti-tumor drugs with independent intellectual property rights in China. It has the advantages of strong anti-tumor activity, wide range of action, mild side effects, and resistance to drug resistance, so it is widely used in the clinical treatment of various malignant tumors. The production of elemene mainly relies on the separation and extraction of the medicinal plant Curcuma wenyujin Y. H. Chen & C. Ling. However, the low content of elemene in the natural materials, complex extracting-process, low product-yield, and high cost, that seriously hinder the large-scale production and the application of elemene. With the development of synthetic biology, constructing cell factories to biosynthesize natural medicines has become a research hotspot, which also provides a new approach for the production of elemene. In recent years, the research on the biosynthesis of elemene has continued to deepen. Researchers have tried to clarify the biosynthesis pathway and key enzymes of elemene by means of metabolic engineering, combinatorial biology, genetic engineering. Some key enzyme genes in the biosynthetic pathway of elemene have been successfully cloned, and the heterologous biosynthesis of elemene has been preliminarily realized. This paper summarizes the elemene biosynthesis pathway and the optimization of engineered bacteria with a review of synthetic biology research thinking, and focuses on the key enzyme gemacrane A synthase (GAS). The optimization strategy of elemene biosynthesis is described, including the overexpression of key rate-limiting enzyme genes, the knockout of shunt genes, the enzymes engineering strategy of fusion expression, and in vitro evolution of key enzyme germacrane A synthetase. The problems and challenges faced in improving the yield of elemene in heterologous biosynthesis were also analyzed. The review will provide a reference for the efficient biosynthesis of elemene.

Development of a liquid-liquid microextraction GC-MS method for simultaneous determination and pharmacokinetic analysis of β- elemene in rat plasma after administration of citronella grass extract / 药学学报

We established a simple and sensitive GC-MS method for the determination of β-elemene in rat plasma and measured the pharmacokinetics of citronella grass extract in rats. Plasma samples were pretreated using liquid-liquid microextraction: 100 μL of plasma sample (containing naphthalene as the internal standard) was extracted with 50 μL of n-hexane. The determination was performed on DB-5ms column (30 m×0.25 mm, 0.25 μm). The initial column temperature was 60 ℃ and raised to 160 ℃ at a rate of 50 ℃·min-1, maintained for 3 min, and finally increased to 260 ℃ for 3 min. Helium was the carrier gas and the flow rate was 0.15 mL·min-1. The injection volume was 2 μL. EI and selected monitored ions pattern were used for ion scanning with m/z 128 (naphthalene) and m/z 93 (β-elemene). Citronella grass extract was administered to rats by intragastric administration and intravenous administration (containing β-elemene 55 mg·kg-1), and plasma was collected and prepared using an automated blood collection system. The linear range of β-elemene in plasma was 1.0-250 ng·mL-1 (r = 0.997), the limit of quantification was 1.0 ng·mL-1, the accuracy was -4.47% - -0.85%, the extraction recovery was between 56.02%-66.89%, and no obvious matrix effect (94.28%-108.63%) was found. The main pharmacokinetic parameters of β-elemene were AUC0-t (23.56 ± 4.40) ng·mL-1, tmax (1.67 ± 0.58) h, Cmax (7.36 ± 0.69) ng·mL-1, MRT0-t (2.76 ± 0.27) h, t1/2z (2.73 ± 1.36) h, Vz (7.39 ± 3.18) L·kg-1, CLz (1.95 ± 0.51) L·h-1·kg-1, and the absolute bioavailability was about 8.78%. The method is simple, accurate, and sensitive, and is suitable for the pharmacokinetic analysis of β-elemene in citronella grass extract in rats. All animal studies were implemented according to protocols, which were reviewed and approved by the Institutional Animal Care and Use Committee at Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences.

Elemene Emulsion Injection Administration Reduces Neuropathic Pain by Inhibiting Astrocytic NDRG2 Expression within Spinal Dorsal Horn / 中国结合医学杂志

OBJECTIVE@#To investigate the mechanisms underlying elemene-induced analgesia in rats with spared nerve injury (SNI).@*METHODS@#Sixty-five rats were equally divided into 5 groups using a random number table: naive group, sham group, SNI group, SNI + elemene (40 mg·kg@*RESULTS@#The SNI rat model exhibited a significant decrease in paw withdrawal threshold and exploratory behaviour in the EPM (P<0.05). Consecutive administration of elemene alleviated SNI-induced mechanical allodynia and anxiety in rats (P<0.05). Immunohistochemical data showed that elemene decreased SNI-induced upregulation of NDRG2 within the SDH (P<0.05). Double immunofluorescent staining data further showed that elemene decreased SNI-induced upregulation of the number of GFAP immunoreactive (-ir), NDRG-ir, and GFAP/NDRG2 double-labelled cells within the SDH (P<0.05). Immunoblotting data showed that elemene decreased SNI-induced upregulation of GFAP and NDRG2 within the SDH (P<0.05).@*CONCLUSION@#Elemene possibly alleviated neuropathic pain by downregulating the expression of NDRG2 in spinal astrocytes in a rat model of SNI.

Treatment with ß-elemene combined with paclitaxel inhibits growth, migration, and invasion and induces apoptosis of ovarian cancer cells by activation of STAT-NF-κB pathway

In this study, we aimed to analyze the anti-cancer effects of β-elemene combined with paclitaxel for ovarian cancer. RT-qPCR, MTT assay, western blot, flow cytometry, and immunohistochemistry were used to analyze in vitro and in vivo anti-cancer effects of combined treatment of β-elemene and paclitaxel. The in vitro results showed that β-elemene+paclitaxel treatment markedly inhibited ovarian cancer cell growth, migration, and invasion compared to either paclitaxel or β-elemene treatment alone. Results demonstrated that β-elemene+paclitaxel induced apoptosis of SKOV3 cells, down-regulated anti-apoptotic Bcl-2 and Bcl-xl gene expression and up-regulated pro-apoptotic P53 and Apaf1 gene expression in SKOV3 cells. Administration of β-elemene+paclitaxel arrested SKOV3 cell cycle at S phase and down-regulated CDK1, cyclin-B1, and P27 gene expression and apoptotic-related resistant gene expression of MDR1, LRP, and TS in SKOV3 cells. In vivo experiments showed that treatment with β-elemene+paclitaxel significantly inhibited ovarian tumor growth and prolonged the overall survival of SKOV3-bearing mice. In addition, the treatment inhibited phosphorylated STAT3 and NF-κB expression in vitro and in vivo. Furthermore, it inhibited migration and invasion through down-regulation of the STAT-NF-κB signaling pathway in SKOV3 cells. In conclusion, the data suggested that β-elemene+paclitaxel can inhibit ovarian cancer growth via down-regulation of the STAT3-NF-κB signaling pathway, which may be a potential therapeutic strategy for ovarian cancer therapy.

Preparation of elemene-loaded mesoporous silica nanoparticles and its targeted anti-tumor activity / 中草药

Objective: To prepare polydopamine-modified elemene-loaded mesoporous silica nanoparticles (D/MSN-ELE), and conduct research on formulation process optimization, quality evaluation, in vitro release, in vitro antitumor activity, and ability to promote apoptosis. Methods: Elemene-loaded mesoporous silica nanoparticles (MSN-ELE) were prepared by solution adsorption method, D/MSN-ELE and polydopamine-modified mesoporous silica nanoparticles (D/MSN) were prepared by polymerization. The morphology of the nanoparticles was characterized by transmission electron microscopy. The PDA graft ratio was calculated by thermogravimetric analysis. The loading and encapsulation efficiency of D/MSN-ELE were evaluated using HPLC, the dialysis bag method was used to investigate the release characteristics in vitro of D/MSN-ELE. MTT staining was used to analyze the cytotoxicity of different nanoparticles on HELF and A549 cells. Flow cytometry was used to detect the levels of D/MSN-ELE reactive oxygen species and mitochondrial membrane potential. Results: The optimal preparation process was the drug loading ratio of 6:1, the temperature was 50℃, and the time was 8 h. The D/MSN-ELE prepare under the process condition have a were uniform distribution with a particle size of (288.70 ± 3.88) nm. The average drug loading and encapsulation efficiency were (11.58 ± 0.73)% and (59.82 ± 0.57)%, respectively. In vitro drug release was pH-responsive, and cumulative drug release increased with decreasing pH. The half-lethal concentrations of ELE, MSN-ELE and D/MSN-ELE on A549 cells were 91.29, 27.56 and 6.02 μg/mL, respectively. The detection results of reactive oxygen species and mitochondrial membrane potential further indicated that drug-loaded nanoparticles were able to promote tumor target cell apoptosis. Conclusion: D/MSN-ELE under the optimized process has a higher drug loading, pH-responsive drug release and greatly enhanced antitumor activity. This study provides further experiments basis for tumor-targeted delivery of elemene drugs based on mesoporous silica nanoparticles.

Research progress on synthesis of intermediates in derivatization of β-elemene / 中草药

β-Elemene is the main active ingredient of elemene, a broad-spectrum anti-cancer botanical drug, which is also the main isomer of elemene's four isomers. The synthesis of some key intermediates were generalized and summarized during the derivatization of β-elemene, wherein the preparation methods, reaction conditions, yields, characterization data of these intermediates were listed. The purpose of this paper is to facilitate people in understanding and grasping the most optimal synthesis of these intermediates up to date, to inspire people pursuing further synthesis improvement, and to stimulate generation of new ideas for future derivatization of β-elemene.

β-Elemene improves endothelial cells dysfunction, and abnormal proliferation and migration of vascular smooth muscle cells / 中国药科大学学报

@#This study aimed to investigate whether β-elemene could improve the dysfunction of vascular endothelial cells induced by low shear force (LSS), and the proliferation and migration of vascular smooth muscle cells induced by oxidized low-density lipoprotein (ox-LDL). Parallel plate flow chambers and ox-LDL were used to establish vascular endothelial cells (ECs) dysfunction model and vascular smooth muscle cell (VSMCs) proliferation and migration model, respectively, and the effects of β-elemene on ECs dysfunction and VSMCs proliferation and migration were examined. The activity of ROS in ECs was measured by DHE and the activity of NO in ECs was tested by DAF-FM DA. The protein phosphorylation of Akt and ERK in ECs were detected by Western blot. The proliferation of VSMCs was measured by MTT. The migration of VSMCs was examined by cell scratch test and Transwell assay. The gene expression of MMP-2 and MMP-9 in VSMCs was measured by RT-qPCR. In ECs, β-elemene could significantly reduce the LSS-induced increase in ROS, significantly increase the LSS-induced decrease in NO, decrease the phosphorylation of ERK, and increase the phosphorylation of Akt. In VSMCs, β-elemene could significantly reduce the proliferation and migration of VSMCs induced by ox-LDL, and reduce the gene expression of MMP-2 and MMP-9. To conclude, β-elemene can improve the LSS-induced ECs dysfunction and ox-LDL-induced VSMCs proliferation and migration.

Bioinsecticide potential of Curcuma zedoaria rhizome essential oil / Potencial bioinseticida do óleo essencial dos rizom as de curcuma zedoaria

In this study the potential bioinseticide of the essential oil (OE) extracted from the rhizomes of the species Curcuma zedoaria (Zingiberaceae) was evaluated. The rhizomes were collected during dormancy (winter) and budding (summer). The EO was obtained by hydrodistillation (2h) and identified by GC/MS. In addition, a multivariate exploratory analysis was done to determine the analysis of the major compounds (PCA). The EO yield in dormancy was 0.61± 0.07 (%) and in budding 0.55 ± 0.08 (%). The bioassays on Aedes aegypti larvae and pupae were done by immersion test at different EO concentrations which ranged from 500.00 to 0.003 mg mL-1 (v/v). The results on the larvae and pupae indicated LC99.9 of (0.01 and 1.38 mg mL-1) for EO in dormancy, and (0.08 and 2.63 mg mL-1) for EO during budding, respectively. The action mechanism of EOs in both periods was determined by autobiographic method evaluating the inhibitory potential on the acetylcholinesterase enzyme, indicating greater inhibition of the EO enzyme during dormancy (0.039 mg mL-1) when compared to the EO during budding (0.156 mg mL-1). The projection representation of the EO chemical classes in both evaluated periods indicated that oxygenated sesquiterpenes are the major compound class (46.99% in dormancy) and (43.59% in budding). The projection of major chemical compounds of EOs presented three compounds with greater mass flow distancing: epicurzerenone (18.20% and 12.10%); 1.8 cineole (15.76% and 12.10%) and ß-elemene (4.43 and 0.01%) that are found in greater amounts in the dormancy EO when compared to budding, respectively. These results corroborate with the greater potential on Ae. aegypti larvae and pupae found for the dormancy EO. The results are promising because they show in which vegetative cycle phase C. zedoaria EO presents greater bioinsecticidepotential.

Neste trabalho foi avaliado o potencial bioinseticida do óleo essencial (OE) extraído dos rizomas da espécie Curcuma zedoaria (Zingiberaceae), coletados no período de dormência (inverno) e brotação das gemas (verão). O OE foi obtido por hidrodestilação (2h) e identificado por CG/EM foi observado rendimento 0,61 ± 0,07 (%) no óleo da dormência, quando comparado no período de brotação 0,55 ± 0,08 (%). Os bioensaios sobre as larvas e pupas de Aedes aegypti foram realizados pelo teste de imersão em diferentes concentrações dos OEs, que variaram de 500,00 a 0,003 mg mL-1 (v/v). Os resultados sobre as larvas e pupas indicaram uma CL99,9 de (0,01 e 1,38 mg mL-1) para o OE da dormência, e (0,08 e 2,63 mg mL-1) para o OE do período de brotação, respectivamente. Indicando maior atividade do OE da dormência. O mecanismo de ação dos OEs nos dois períodos foi determinado pelo método autobiográfico avaliando o potencial inibitório sobre a enzima acetilcolinesterase. Os resultados indicaram maior inibição da enzima do OE no período de dormência (0,039 mg mL-1), quando comparado ao OE de brotação (0,156 mg mL-1). A análise química destacou três compostos: epicurzerenone (18,20% e 12,10%) e 1,8 cineol (15,76% e 14,05%) e ß- elemeno (4,43 e 0,01%) em maior quantidade no período de dormência quando comparado ao período de brotação, respectivamente. Esta diferença pode explicar a maior ação inseticida do OE de dormência sobre as larvas e pupas do Ae. aegypti. Os resultados são promissores, pois estabelece em qual período do ciclo vegetativo o OE da C. zedoaria apresenta maior potencial bioinseticida.

Transferrin-functionalized co-delivery microemulsion of β-elemene and celastrol for synergistic anti-colorectal cancer treatment / 中草药

Objective To verify the synergistic effect of transferrin modified β-elemene and celastrol co-loaded microemulsion (Tf-EC-MEs) on anti-colorectal cancer treatment. Methods The optimal mass ratio of β-elemene and celastrol to growth inhibition of Lovo and HT-29 colorectal cancer cells was optimized by MTT staining method in vitro. Tf-EC-MEs was prepared by “mixing-dripping” method, and the preparation and physicochemical properties of the particles were characterized by high performance liquid chromatography (HPLC), laser particle analyzer, and transmission electron microscope. The MTT staining, HPLC-BCA combined method, and Annexin V-PE/7-Aminoactinomycin D (Annexin V-PE/7-AAD) kit were used to investigate the antitumor activity of Tf-EC-MEs in vitro, and its effect on cell uptake, and apoptosis of tumor cells. The tumor-bearing nude mice model was established by subcutaneous injection of Lovo cells, and the tumor growth, weight, and survival time were observed after intravenous injection of β-elemene + celastrol, β-elemene-celastrol co-loaded microemulsion (EC-MEs), and Tf-EC-MEs. Results The combined administration of β-elemene and celastrol (40:1) had significant synergistic effect on the anti-colorectal cancer of Lovo and HT-29 cells. IC50 of β-elemene + celastrol in Lovo and HT-29 cells were (17.5 ± 2.9) and (36.4 ± 3.6) μg/mL, with the CI as 0.89 and 0.96, respectively. IC50 of Tf-EC-MEs in Lovo and HT-29 cells were (11.7 ± 0.6) and (27.4 ± 1.2) μg/mL, with the CI as 0.61 and 0.72 respectively. The 4 h of Lovo uptake of Tf-EC-MEs was 7.2 μg/mg, which was 3.3 times higher than that of β-elemene + celastrol. Tf-EC-MEs induced apoptosis in 59.2% of Lovo cells, which was significantly higher than that in beta-elemene + celastrol and EC-MEs groups. Tf-EC-MEs showed the overwhelming inhibition of growth of Lovo tumor-bearing tumors. The survival rate of Tf-EC-MEs-treated mice was 37.5% at day 60. In Tf-EC-MEs treated group, HE staining sections of tumor tissues showed substantial cell necrosis and the Ki-67 immunohistochemical sections displayed the significant inhibition of proliferation of tumor cells. Conclusion Compared with the combination group (beta-elemene and celastrol) and EC-MEs groups, Tf-EC-MEs has a promising potential in the synergistic anti-colorectal cancer treatment.

Clinical observation on the effect of elemene injection maintenance treatment on the recurrence time of malignant pleural effusion / 国际肿瘤学杂志

Objective To observe the effect of elemene injection for the maintenance treatment of malignant pleural effusion.Methods A total of 90 patients with malignant pleural effusion from May 2014 to Apirl 2016 in First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine were collected.They were divided into observation group (n =45) and control group (n =45) according to the random number table method.The patients of the two groups were treated with pleural effusion drainage through thoracocentesis,and Mannatide (Lifein) and carboplatin were poured.The observation group sequentially received maintenance treatment of elemene injection.The therapeutic effects of the two groups were compared.Results At the 12th month after treatment,the difference of relapse rate between the two groups was statistically significant(82.2％ vs.100.0％,x2 =8.780,P =0.003).The median progression-free survival (95％ CI) of the observation group and the control group were 10.00 (9.15-10.85) months and 6.00(4.74-7.26) months respectively,with a significant difference (x2 =40.475,P ＜ 0.001).The improvement rates of life quality of the observation group were 82.22％,57.78％,54.55％ respectively at one,six,twelve months after perfusion treatment,and the improvement rates of the control group were 84.44％,23.26％,0 respectively.The data differences between the two groups were statistically significant at six,twelve months (x2 =10.840,P =0.001;x2 =32.390,P ＜ 0.001).The one year survival rates of the observation group and the control group were 97.78％ and 95.56％,and the difference was statistically significant (P =1.000).Conclusion The effect of elemene injection for the maintenance treatment of malignant pleural effusion is obvious,which can prolong the progression-free survival time and can significantly improve the quality of life.

Effects of Elemene Injection on the kinetics of intracellular transport of Gefitinib in PC-9/GR cells / 中成药

AIM To study the effects of Elemene Injection (ELE) on the kinetics of intracellular transport of Gefitinib (GEF) in PC-9/GR cells and to probe the role of ELE in reversing oncological multidrug resistance.METHODS The intracellular pharmacokinetic behavior of D-luciferin potassium salt,a substrate of an ATP-binding cassette (ABC) protein,was investigated in PC-9/GRFluc cells using real-time bioluminescence imaging.The resistance of PC-9/GR cells to GEF was determined by MTT assay.Compusyn software was used to analyze the synergistic effect of GEF and ELE,and HPLC to detect the uptake of GEF in PC-9/GR cells.RESULTS The respective GEF IC50 values of 0.01 μg/mL in PC-9 cells and 1.50 μg/mL in PC-9/GR cells revealed the 150 times drug resistance of PC-9/GR to PC-9 cells.The significantly enhanced intracellular fluorescence intensity of D-fluorescein potassium salt by the intervention of ELE also indicated remarkable GEF uptake increase in PC-9/GR cell line (P ＜ 0.05) due to the synergistic result.CONCLUSION Partly as the mechanism in reversing oncological multidrug resistance,ELE,a booster for the fluorescence intensity of D-luciferin potassium salt,promotes cellular uptake of GEF by inhibiting efflux function of ABC proteins.

Severe Adverse Reactions Induced by the Chest Injection of Elemene: An Analysis of 7 Cases / 中国肺癌杂志

BACKGROUND@#Malignant pleural effusion (MPE) refers to pleural effusion which arises from primary malignant tumor of pleura or other pleural metastatic tumors. Injection of elemene in chest makes good effect on the treatment of MPE, and is widely used in clinic. Adverse effects also exist, but the severe adverse effects and relevant managements are rarely reported. The aim of this study is to observe the adverse reactions induced by the treatment of malignant pleural effusion through elemene injection and to explore the solutions.@*METHODS@#A retrospective analysis was made on 14 cases of patients receiving intra-pleural injections with elemene, and the incidence of severe adverse reactions of 7 cases were disscussed in detail.@*RESULTS@#Most of the severe adverse reactions caused by elemene were severe chest pain, dyspnea, wheezing, clouding of consciousness and coagulopathy.@*CONCLUSIONS@#Strict screening, full preprocessing and close monitoring are necessary to prevent serious adverse reactions caused by elemene injection in the treatment of malignant pleural effusion.

Advance in research on anticancer drug β-elemene and its derivatives / 中草药

β-elemene is the sesquiterpene active monomer, as a national second-class non-cell toxic antitumor drugs which extracted from Zingiberaceae Curcuma rcenyujin. Moreover, β-elemene is currently used in clinic for treatment of lung cancer, liver cancer as well as breast cancer, and so on. Because of its broad-spectrum, safe, efficient, economical and other outstanding advantages in antitumor activities, leading to a broad application prospect in clinic. With the deep study of component and anticancer mechanisms of β-elemene, in order to promote its bioavailability and anticancer activity, researchers have screened a great deal of significant effective derivatives, and designed its liposome, microemulsion and other new drug delivery systems, which provide scientific theoretical guidance for further development and utilization of β-elemene. In this study, a systematic illustration was made for the current advance of pharmacological effects and mechanisms of β-elemene on treating cancer. In addition, the important derivatives, new drug delivery systems, and adverse reactions of β-elemene also be clarified, aiming to provide ideas for further scientific research and innovation of β-elemene.

β-elemene reverses hepatocyte growth factor-induced resistance to ge-fitinib in PC-9 lung cancer cells via c-Met pathway / 中国病理生理杂志

AIM:To investigate the effect of β-elemene on reversing hepatocyte growth factor(HGF)-induced resistance to gefitinib in PC-9 cells, and to explore its possible mechanisms.METHODS: The gefitinib-resistant PC-9 cells induced by HGF were treated with β-elemene or/and gefitinib.The cell activity was measured by MTT assay.The effect of β-elemene on the invasion ability in HGF-induced resistance to gefitinib in PC-9 cells was detected by Transwell migration assay.The protein levels of p-Met, c-Met, p-AKT and AKT in PC-9 cells of each group were determined by Western blot.RESULTS:The results of MTT assay showed that the cell activity of PC-9 cells was significantly inhibited by β-elemene(P<0.05).IC50of β-elemene for PC-9 cells was 169.31 mg/L.IC50of gefitinib for PC-9 cells was 0.30 μmol/L.Exogenously adding recombinant HGF induced significantly resistance to gefitinib in PC -9 cells.Moreover, SU11274(an inhibitor of c-Met)significantly decreased the viability of the cells exposed to HGF and gefitinib(P <0.05).Combined treatment with β-elemene and gefitinib in the presence of HGF(50 μg/L)significantly decreased the viability of PC-9 cells as compared with the PC-9 cells treated with gefitinib alone in the presence of HGF(P<0.05),so did the result of the cell migration.The protein levels of p-Met and p-AKT were significantly up-regulated by HGF,while the protein levels of p-Met and p-AKT were markedly down-regulated in the cells treated with β-elemene and gefitinib com-pared with gefitinib alone in the presence of HGF.CONCLUSION: β-elemene reverses HGF-induced resistance to ge-fitinib in lung cancer PC-9 cells,likely due to the inhibition of HGF-induced activation of c-Met and its down streams sig-naling pathways(P<0.01).

Essential oil of Pterodon polygalaeflorus Benth attenuates nociception in mice

Essential oils (EO) are volatile liquids responsible for the aroma of plants. Pterodon polygalaeflorus seeds have received widespread use in folk medicine for the treatment of inflammatory diseases. For this reason and because Pterodon polygalaeflorus seeds have great EO content, which is frequently pharmacologically active, the present study aimed to evaluate the antinociceptive effect of EO from Pterodon polygalaeflorus (EOPPgfl) and its acute toxic effects. The EEOPPgfl sample, which was extracted by steam distillation of the seeds, had a yield of 2.4% of the seeds weight and had, as major constituents, beta-elemene (48.19%), trans-caryophyllene (19.51%), and epi-bicyclosesquiphellandrene (12.24%). The EOPPgfl sample showed mild acute toxicity and its calculated median lethal dose (LD50) was 3.38 g/kg. EOPPgfl (20-60 mg/kg) showed antinociceptive activity as evidenced by several tests and inhibited writhing induced by acetic acid. The maximum effect was obtained with the 30 mg/kg dose and at 60 min after its administration. EOPPgfl also decreased formalin-induced nociception, as verified by the inhibition of the first and second phase of the formalin test. At 30 mg/kg, EOPPgfl also decreased thermally stimulated nociception. Nociception may be related to inflammatory and antiedematogenic activity and at doses ranging 10-100 mg/kg, EOPPgfl blocked dextran- and carrageenan-induced edema. The results demonstrated that EOPPgfl presented, at doses approximately 100 times smaller than LD50, an antinociceptive effect that probably was due to anti-inflammatory activities.

Systematic Evaluation of Elemene Combined with Radiotherapy for Intervention in Brain Metastasis from Pulmonary Neoplasms / 中国中医药信息杂志

Objective To systematically evaluate the effectiveness and safety of Elemene combined with radiotherapy for intervention in brain metastasis from pulmonary neoplasms. Methods Articles of clinical randomized controlled trials about Elemene combined with radiotherapy for intervention in brain metastasis from pulmonary neoplasms from the establishment of the databases to October of 2016 from CNKI, CBM, Chongqing Weipu, Wanfang database, Cochrane Library, PubMed and Embase were retrieved by computers. Bias risk assessment tools in Cochrane systematic evaluation handbook 5.1.0 was used to conduct quality evaluation for included articles. RevMan5.3 software was used to carry out Meta-analysis. Results Totally 12 articles and 839 patients were included. Results of Meta-analysis showed that Elemene combined with radiotherapy had more obvious curative effect on narrowing the neoplasm compared with pure radiotherapy [OR=2.73, 95%CI (1.97, 3.77), P<0.000 01], and improve patients' life quality at the same time [OR=3.85, 95%CI (2.23, 6.65), P<0.000 01], and relieve adverse reactions [OR=4.16, 95%CI (2.40, 7.22), P<0.000 01]. Conclusion Elemene combined with radiotherapy for intervention in brain metastasis from pulmonary neoplasms shows confirmed efficacy, and is relatively safe. But whether the program should be widely used in clinic, more large sample, multi-center, and high-quality clinical randomized controlled trials are still needed.