beta-elemene and Carcinoma--Non-Small-Cell-Lung

To evaluate the effectiveness and safety of β-elemene Injection as an adjunctive treatment for lung cancer by systematic review.. We retrieved randomized controlled clinical trials related to the use of β-elemene Injection as an adjunctive treatment for lung cancer from Chinese Biomedical (CBMweb), Chinese Medical Current Content (CMCC), China National Knowledge Infrastructure (CNKI), ChinaInfo, Cochrane Central Register of Controlled Trials; MEDLINE, EMBASE, OVID and TCMLARS. We also referred to an unpublished conference proceeding titled Clinical Use and Basic: Elemene Injection. We then divided the studies into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) subgroups by RevMan 5.1 software.. A total of 21 source documents (1,467 patients) matched pre-specified criteria for determining the effectiveness and safety of β-elemene Injection as an adjunctive treatment for lung cancer. Five studies involving 285 NSCLC patients reported a higher 24-month survival rate (39.09%) with the adjunctive treatment than with chemotherapy alone (26.17%; RR, 1.51; 95% CI, 1.03 to 2.21). Four studies involving 445 patients reported that the increased probability for improved performance status for patients treated with elemene-based combinations was higher than that of patients treated with chemotherapy alone (RR, 1.82; 95% CI, 1.45 to 2.29). The results from a subgroup analysis on 12 studies involving 974 NSCLC patients and 9 studies involving 593 patients with both SCLC and NSCLC showed that the tumor control rate for NSCLC improved more in the elemene-based combinations treatment group (78.70%) than in the chemotherapy alone control group (71.31%; RR, 1.06; 95% CI, 1.00 to 1.12). The tumor response rate for NSCLC also improved more among patients treated with elemenebased combinations (50.71%) than among patients treated with chemotherapy alone (38.04%; RR, 1.34; 95%CI, 1.17 to 1.54). In addition, the main adverse reaction to β-elemene Injection was phlebitis, but usually only to a mild degree. An Egger's test showed no publication bias in our study (P=0.7030).. The effectiveness of chemotherapy for the treatment of lung cancer may improve when combined with β-elemene injection as an adjunctive treatment. The combined treatment can result in an improved quality of life and prolonged survival. However, these results require confirmation by rigorously controlled trials.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Combined Modality Therapy; Drugs, Chinese Herbal; Humans; Injections; Lung Neoplasms; Sesquiterpenes; Small Cell Lung Carcinoma

Nearly half of all Asian non-small cell lung cancer (NSCLC) patients harbour epidermal growth factor receptor (EGFR) mutations, and first-generation EGFR tyrosine kinase inhibitors (TKIs) are one of the first-line treatments that have improved the outcomes of these patients. Unfortunately, 20% of these patients can not benefit from the treatment. The basis of this primary resistance is poorly understood. Therefore, overcoming EGFR-TKI primary resistance and maintaining the efficacy of TKIs has become a key issue. β-Elemene, a sesquiterpene compound extracted from Curcuma aromatica Salisb. (wenyujing), has shown potent antitumor effects. In this research, we found that β-elemene combined with erlotinib enhanced the cytotoxicity of erlotinib to primary EGFR-TKI-resistant NSCLC cells with EGFR mutations and that ferroptosis was involved in the antitumor effect of the combination treatment. We found that lncRNA H19 was significantly downregulated in primary EGFR-TKI-resistant NSCLC cell lines and was upregulated by the combination treatment. Overexpression or knockdown of H19 conferred sensitivity or resistance to erlotinib, respectively, in both in vitro and in vivo studies. The high level of H19 enhanced the cytotoxicity of erlotinib by inducing ferroptosis. In conclusion, our data showed that β-elemene combined with erlotinib could enhance sensitivity to EGFR-TKIs through induction of ferroptosis via H19 in primary EGFR-TKI-resistant lung cancer, providing a promising strategy to overcome EGFR-TKI resistance in NSCLC patients.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Ferroptosis; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; RNA, Long Noncoding; Sesquiterpenes

Topics: Aldehyde Dehydrogenase; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Energy Metabolism; Humans; Hypoxia; Lung Neoplasms

β-Elemene is the main active ingredient in Curcumae Rhizoma that exerts antitumour effects. Anoikis affects tumour development through various biological pathways in non-small cell lung cancer (NSCLC), but the regulation between β-elemene and anoikis remains to be explored. First, we explored the molecular expression patterns of anoikis-associated genes (AAGs) using consensus clustering and characterized the impact of AAGs on patient prognosis, clinical characteristics, and genomic instability. In addition, we revealed that AAG regulatory genes have rich interactions with β-elemene targets, and established a lncRNA-miRNA-mRNA network to explain the effect of β-elemene on anoikis. Finally, to reveal the prognostic effect of their correlation, the prognostic scoring model and clinical nomogram of β-elemene and anoikis were successfully established by least absolute shrinkage and selection operator (LASSO) and random forest algorithms. This prognostic scoring model containing noncoding RNA (ncRNA) can indicate the immunotherapy and mutational landscape, providing a novel theoretical basis and direction for the study of the antitumour mechanism of β-elemene in NSCLC patients.

Topics: Anoikis; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; MicroRNAs; Prognosis; RNA, Long Noncoding; RNA, Messenger

β-elemene has been evidenced to suppress the development of numerous cancers including lung cancer. Previous research has found that in A549 cells, β-elemene increased the expression of adenosine monophosphate-activated protein kinase (AMPK) α (AMPKα), which negatively regulates the Warburg effect. Bioinformatics predicted that binding sites exist between AMPKα and miR-301a-3p, an miRNA that has shown oncogenic function in many cancers. The aim of this work was to investigate the effect of β-elemene on the Warburg effect in non-small-cell lung cancer (NSCLC) cells and its mechanism. Herein, the expression of miR-301a-3p was evaluated in NSCLC cells. Then, miR-301a-3p was overexpressed or silenced by mimics or inhibitors, respectively, followed by treatment with AMPK agonists or antagonists. NSCLC cells subjected to miR-301a-3p overexpression or inhibition were further treated with β-elemene. The results demonstrated that AMPKα was targeted and negatively regulated by miR-301a-3p. AMPKα agonists attenuated the Warburg effect in NSCLC cells induced by miR-301a-3p, as evidenced by the decrease in glucose level, lactic acid level, and expression of metabolism-related enzymes (glucose transporter 1 (GLUT1), hexokinase 1 (HK1), and lactate dehydrogenase A (LDHA)). Additionally, β-elemene suppressed the expression of miR-301a-3p, enhanced that of AMPKα, and inhibited the Warburg effect in NSCLC cells. The results indicated that β-elemene attenuates the Warburg effect in NSCLC cells, possibly by mediating the miR-301a-3p/AMPKα axis.

Topics: A549 Cells; AMP-Activated Protein Kinases; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glucose Transporter Type 1; Hexokinase; Humans; L-Lactate Dehydrogenase; Lung Neoplasms; MicroRNAs; Sesquiterpenes; Signal Transduction; Warburg Effect, Oncologic

N

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Female; Gefitinib; Humans; Lung Neoplasms; Methyltransferases; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Molecular; Random Allocation; Sesquiterpenes; Xenograft Model Antitumor Assays

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Homeodomain Proteins; Humans; Lung Neoplasms; NF-kappa B; Nitric Oxide Synthase Type II; Radiation Tolerance; Radiation-Sensitizing Agents; Sesquiterpenes; Signal Transduction

Endoplasmic reticulum stress (ERs) has been regarded as an important cause for the pathogenesis of non-small-cell lung cancer (NSCLC). β-elemene is an active component in the essential oil extracted from a medicinal herb, Curcuma wenyujin, and has been reported to be effective against non-small-cell lung cancer (NSCLC). However, the potential effect and underlying mechanisms of β-elemene on regulating ERs to inhibit NSCLC are still unclear. In the present study, A549 cells and Lewis tumor-bearing C57BL/6J mice were established to evaluate this effect. Visualsonics Vevo 2100 Small Animal Dedicated High-frequency Color Ultrasound was performed to observe tumor volume in vivo. 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) was used to evaluate cell vitality of A549 cells. Furthermore, western blotting (WB), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (q-PCR) were applied to detect the ERs-related proteins. Flow cytometry was also applied to detect cell apoptosis and assay kit for reactive oxygen species (ROS) generation. Our results showed that β-elemene inhibited lung cancer tumor growth and cell vitality in a dose- and time-dependent manner. Not only that, β-elemene could up-regulate ERs-related proteins like PERK, IRE1α, ATF6, ATF4, CHOP and down-regulate the Bcl-2 expression. More importantly, ERs inhibitor 4-PBA, IRE1α inhibitor STF-083010, ATF6 inhibitor Anti-ATF6 and PERK inhibitor GSK2656157 can all reduce the amplitude of protein expression changes and apoptosis rates, then weaken the anti-tumor effect of β-elemene. Therefore, the present in vivo and in vitro study revealed that the anti-NSCLC effect of β-elemene is closely related to the activation of ERs through PERK/IRE1α/ATF6 pathway, and this might be beneficial for clinical therapy of NSCLC.

Topics: A549 Cells; Activating Transcription Factor 6; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Survival; eIF-2 Kinase; Endoplasmic Reticulum Stress; Endoribonucleases; Humans; Lung Neoplasms; Mice, Inbred C57BL; Models, Biological; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Sesquiterpenes; Signal Transduction; Time Factors; Transcription Factor CHOP

β-elemene, a compound derived from Rhizoma zedoariae, is a promising new plant-derived drug with broad-spectrum anticancer activity. However, the underlying mechanism by which this agent inhibits human lung cancer cell growth has not been well elucidated. In this study, we showed that β-elemene inhibits human non-small cell lung carcinoma (NSCLC) cell growth, and increased phosphorylation of ERK1/2, Akt and AMPKα. Moreover, β-elemene inhibited expression of DNA methyltransferase 1 (DNMT1), which was not observed in the presence of the specific inhibitors of ERK (PD98059) or AMPK (compound C). Overexpression of DNMT1 reversed the effect of β-elemene on cell growth. Interestingly, metformin not only reversed the effect of β-elemene on phosphorylation of Akt but also strengthened the β-elemene-reduced DNMT1. In addition, β-elemene suppressed Sp1 protein expression, which was eliminated by either ERK1/2 or AMPK inhibitor. Conversely, overexpression of Sp1 antagonized the effect of β-elemene on DNMT1 protein expression and cell growth. Taken together, our results show that β-elemene inhibits NSCLC cell growth via ERK1/2- and AMPKα-mediated inhibition of transcription factor Sp1, followed by reduction in DNMT1 protein expression. Metformin augments the effect of β-elemene by blockade of Akt signalling and additively inhibition of DNMT1 protein expression. The reciprocal ERK1/2 and AMPKα signalling pathways contribute to the overall responses of β-elemene. This study reveals a potential novel mechanism by which β-elemene inhibits growth of NSCLC cells.

Topics: AMP-Activated Protein Kinases; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Humans; Lung Neoplasms; MAP Kinase Signaling System; Metformin; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA Interference; RNA, Small Interfering; Sesquiterpenes; Sp1 Transcription Factor

Schinifoline (SF), a 4-quinolinone derivative, was found in Zanthoxylum schinifolium for the first time. 4-Quinolinone moieties are thought to have cytotoxic activity and are often used as a tubulin polymerization inhibitors, heterogeneous enzyme inhibitors and antiplatelet agents. However, very little information respect to radiosensitization has focused on SF. This work aimed to investigate the radiosensitizing effect of SF on A549 cells. The cell viability results indicated cytotoxicity of SF on A549 cells, with IC50 values of 33.7 ± 2.4, 21.9 ± 1.9 and 16.8 ± 2.2 μg/mL, respectively, after 6, 12, 24 h treatment with different concentrations, and the 10% or 20% IC50 concentration during 12 h was applied in later experiments. The results of cell proliferative inhibition and clonogenic assay showed that SF enhanced the radiosensitivity of A549 cells when applied before 60Co γ-irradiation and this effect was mainly time and concentration dependent. The flow cytometric data indicated that SF treatment before the irradiation increased the G2/M phase, thus improving the radiosensitivity of A549, leading to cell apoptosis. This paper is the first study that describes the in vitro radiosensitising, cell cycle and apoptotic-inducing effects of schinifoline.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Gamma Rays; Humans; Lung Neoplasms; Quinolones; Radiation-Sensitizing Agents; Radiation, Ionizing; Sesquiterpenes; Tumor Stem Cell Assay; Zanthoxylum

The development of effective agents for overcoming platinum chemoresistance in lung carcinoma continues to have high priority. We have demonstrated recently that β-elemene, a novel antitumor compound, enhances cisplatin activity by triggering lung cancer cell death via apoptosis. Here, we investigated whether β-elemene acts synergistically with cisplatin to inhibit non-small cell lung cancer (NSCLC) cell proliferation by blocking cell cycle progression. β-Elemene substantially increased the suppressive effect of cisplatin on cell growth and proliferation in the NSCLC cell lines H460 and A549. Furthermore, β-elemene augmented cisplatin in the cell cycle arrest of NSCLC cells at G(2)/M. This was associated with upregulated checkpoint kinase (CHK2) expression and reduced CDC2 activity (i.e., increased phosphorylation of CDC2 on Tyr-15 and decreased phosphorylation of CDC2 on Thr-161). Moreover, β-elemene and cisplatin in combination clearly decreased the protein levels of cyclin B1 and CDC25C and increased the levels of p21(Cip1/Waf1), p27(Kip1), and GADD45 in these cells, compared with the effects of either agent alone at the same concentration. These results suggest that the β-elemene-enhanced inhibitory effect of cisplatin on lung carcinoma cell proliferation is regulated by a CHK2-mediated CDC25C/CDC2/cyclin B1 signaling pathway and leads to the blockade of cell cycle progression at G(2)/M. A comparison of the cytotoxic efficacies of β-elemene and three synthetic analogs (β-elemenol, β-elemenal, and β-elemene fluoride) in the two lung cancer cell lines revealed that β-elemenol and β-elemene fluoride had the same antitumor efficacy as β-elemene, whereas β-elemenal was appreciably more potent than β-elemene. Thus, although all three synthetic analogs of β-elemene considerably suppressed NSCLC cell growth and proliferation, β-elemenal may have greater potential as an anticancer alternative to β-elemene in treating lung cancer and other tumors.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; CDC2 Protein Kinase; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 2; Cisplatin; Cyclin B; Cyclin-Dependent Kinases; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; Phosphorylation; Protein Serine-Threonine Kinases; Sesquiterpenes

β-Elemene, a novel traditional Chinese medicine, has been shown to be effective against a wide range of tumours. In this study, the antitumour effect of β-elemene on human non-small-cell lung cancer (NSCLC) A549 cells and the mechanism involved have been investigated.. Cell viability and apoptosis were measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. Protein expression was assayed by Western blotting. Autophagy was evaluated under fluorescence microscopy and transmission electron microscopy.. β-Elemene inhibited the viability of A549 cells in a dose-dependent manner. This suppression of cell viability was due to the induction of apoptosis. Further study showed that β-elemene inhibited the activity of the PI3K/Akt/mTOR/p70S6K1 signalling pathway, and at the same time it triggered a robust autophagy. The autophagy was characterized by the accumulation of punctate LC3 dots in the cytoplasm, morphological changes, and the increased levels of LC3-II as well as Atg5-Atg12 conjugated proteins. Inhibition of autophagy with chlorochine significantly enhanced the antitumour effect of β-elemene.. Our data indicated that β-elemene inhibited the activity of the PI3K/Akt/mTOR/p70S6K1 signalling pathway in human NSCLC A549 cells, which resulted in apoptosis as well as protective autophagy. A combination of β-elemene with autophagy inhibitor might be an effective therapeutic option for advanced NSCLC.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Carcinoma, Non-Small-Cell Lung; Drugs, Chinese Herbal; Humans; Lung Neoplasms; Phytotherapy; Sesquiterpenes

beta-Elemene, a new plant-derived anticancer agent with low toxicity, has been reported to be effective in the treatment of leukemia and solid tumors. In the current study, we explored the therapeutic application of beta-elemene in sensitizing lung cancer cells to cisplatin. beta-Elemene considerably enhanced the inhibitory effect of cisplatin on cell proliferation in a time- and dose-dependent manner in the human non-small cell lung cancer (NSCLC) cell lines H460 and A549. Furthermore, this effect of beta-elemene on cisplatin activity occurred through the induction of apoptosis in NSCLC cells, as assessed by an ELISA-based assay, TUNEL assay and annexin V binding assay. Consistent with these results, the protein levels of Bax and phospho-Bcl-2 increased and those of Bcl-2 and XIAP decreased in cells treated with beta-elemene in combination with cisplatin, compared with the levels in cells treated with either agent alone. Finally, beta-elemene augmented the cisplatin-induced increases in caspase-3, -7, -9 and -10 activities and cleaved caspase-3, -9 and poly(ADP-ribose) polymerase levels in NSCLC cells. These observations suggest that beta-elemene sensitizes NSCLC cells to cisplatin via a mitochondria-mediated intrinsic apoptosis pathway involving Bcl-2 family proteins and IAPs (inhibitor of apoptosis proteins). Our data provide a rationale for developing a combination of beta-elemene and cisplatin as a regimen for the treatment of lung carcinoma and other cisplatin-resistant tumors.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Line, Tumor; Cell Proliferation; Cisplatin; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Lung Neoplasms; Mitochondria; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Sesquiterpenes; Time Factors; X-Linked Inhibitor of Apoptosis Protein

Beta-elemene is a novel anticancer drug, which was extracted from the ginger plant. However, the mechanism of action of beta-elemene in non-small-cell lung cancer (NSCLC) remains unknown. Here we show that beta-elemene had differential inhibitory effects on cell growth between NSCLC cell lines and lung fibroblast and bronchial epithelial cell lines. In addition, beta-elemene was found to arrest NSCLC cells at G2-M phase, the arrest being accompanied by decreases in the levels of cyclin B1 and phospho-Cdc2 (Thr-161) and increases in the levels of p27(kip1) and phospho-Cdc2 (Tyr-15). Moreover, beta-elemene reduced the expression of Cdc25C, which dephosphorylates/activates Cdc2, but enhanced the expression of the checkpoint kinase, Chk2, which phosphorylates/ inactivates Cdc25C. These findings suggest that the effect of beta-elemene on G2-M arrest in NSCLC cells is mediated partly by a Chk2-dependent mechanism. We also demonstrate that beta-elemene triggered apoptosis in NSCLC cells. Our results clearly show that beta-elemene induced caspase-3, -7 and -9 activities, decreased Bcl-2 expression, caused cytochrome c release and increased the levels of cleaved caspase-9 and poly(ADP-ribose) polymerase in NSCLC cells. These data indicate that the effect of beta-elemene on lung cancer cell death may be through a mitochondrial release of the cytochrome c-mediated apoptotic pathway.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspases; CDC2 Protein Kinase; cdc25 Phosphatases; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cells, Cultured; Checkpoint Kinase 2; Cyclin-Dependent Kinase Inhibitor p27; Cytochromes c; Enzyme Activation; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Lung Neoplasms; Phosphorylation; Poly(ADP-ribose) Polymerases; Protein Serine-Threonine Kinases; Sesquiterpenes; Tumor Suppressor Proteins