beta-elemene and Adenocarcinoma

Elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane) is a naturally occurring compound that can be isolated from the traditional Chinese medicinal herb Curcuma wenyujin. β-elemene, its active component, has recently been demonstrated to enhance the radiosensitivity of human cancer cell lines in vitro and of one animal tumor in vivo. The underlying mechanism, however, is still unclear. In this study, we demonstrated for the first time that β-elemene significantly improves the radiosensitivity of A549 lung adenocarcinoma xenograft in vivo as measured by tumor regrowth delay experiments. Our results showed that β-elemene, at 45 mg/kg, significantly inhibited radiation-induced expression of survivin and hypoxia-inducible factor (HIF)-1 α proteins. Because HIF-1 α is known to regulate survivin transcription and acts as upstream regulator of survivin, it is possible that β-elemene regulates the transcription of survivin through HIF-1 α. Our study suggests that β-elemene is a promising drug to enhance tumor radioresponse, and survivin and HIF-1 α are novel targets of β-elemene.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Cell Line, Tumor; Combined Modality Therapy; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Radiation-Sensitizing Agents; Sesquiterpenes; Survivin; Xenograft Model Antitumor Assays

In the present study, we profiled β‑elemene‑regulated gene expression and investigated the effects of the silencing of the DNA polymerase epsilon 2, accessory subunit (POLE2) in lung cancer cells. Differently expressed genes were profiled in A549 cells incubated in the presence or absence of β‑elemene by Affymetrix Human Gene Expression Array. POLE2 shRNA was then constructed to knock down POLE2 expression. Cells were counted and phenotypes were assessed via CCK‑8, colony formation and caspase-3/-7 activity assays. PathScan antibody array analysis was used to identify shPOLE2‑regulated genes. The cDNA microarray identified a total of 721 differentially expressed genes in the A549 cells. Furthermore, knockdown of POLE2 expression inhibited A549 and NCI‑H1299 cell proliferation and apoptosis. The PathScan data indicated that expression levels of p‑Akt (phosphorylated‑protein kinase B, p‑AKT/p‑PKB), p‑Smad2 (phosphorylated mothers against decapentaplegic homolog 2), p‑p38 MAPK (phosphorylated mitogen‑activated protein kinases p38), p‑SAPK/JNK (phosphorylated c‑Jun N‑terminal protein kinase/stress activated protein kinase), cleaved caspase‑7, IκBα (nuclear factor of κ light polypeptide gene enhancer in B‑cell inhibitor, α), p‑Chk1 (phosphorylated checkpoint kinase 1), p‑IκBα, p‑eIF2α (phosphorylated eukayotic translational initiation factor 2α), p‑TAK1 (phosphorylated TGF‑B‑activated kinase 1), survivin and α‑tubulin were significantly lower in shPOLE2 cells than these levels in the shCtrl cells. The PathScan data indicated that the expression levels of p‑p53 (phosphorylated tumor protein 53) were significantly higher in the shPOLE2 cells than these levels in the shCtrl cells. β‑elemene can restrain human lung cancer A549 and NCI‑H1299 cell proliferation and apoptosis by suppressing POLE2 expression.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; DNA Polymerase II; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Oligonucleotide Array Sequence Analysis; RNA, Small Interfering; Sesquiterpenes; Up-Regulation

β-elemene, the active component of elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane), is a naturally occurring compound isolated from the traditional Chinese medicinal herb Curcuma wenyujin. Studies have confirmed that β-elemene enhances the radiosensitivity of lung cancer cell lines such as A549, by multiple pathways; however, their underlying mechanisms and pathways are yet to be elucidated. In the present study, two-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry were used to profile the different proteins in A549 cell xenograft models of both treatment groups. The protein/mRNA expression was assessed by reverse transcription-polymerase chain reaction and western blotting techniques in tumor samples from all treatment groups. As a critical player in redox regulation of cancer cells, inhibition of peroxiredoxin-1 (Prx-1) may be an effective option for enhancing the tumor response to radiation. We further verified Prx-1 expression at the transcription and translation levels. β-elemene at a dose of 45 mg/kg had little effect on the Prx-1 protein expression, which was correlated with a moderate antitumor effect. However, a 45 mg/kg dose of β-elemene significantly inhibited the Prx-1 mRNA expression, thereby suggesting a possible influence on the transcriptional process, and radiation significantly increased the Prx-1 mRNA/protein expression compared to the control group (p<0.01). Notably, Prx-1 mRNA/protein expression was significantly lower in the β-elemene/radiation co-treatment group compared to the baseline levels in the control group (p<0.01). These results suggest that radiation-induced Prx-1 expression is directly or indirectly suppressed by β-elemene, thus suggesting a new pathway by which to reverse radioresistance.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Cell Line, Tumor; Curcuma; Down-Regulation; Female; Humans; Lung Neoplasms; Medicine, Chinese Traditional; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Peroxiredoxins; Plant Extracts; Radiation Tolerance; Radiation-Sensitizing Agents; Radiography; RNA, Messenger; Sesquiterpenes; Tandem Mass Spectrometry; Transcription, Genetic; Transplantation, Heterologous

The purpose of this manuscript was to study the regulation effects of β-elemene combined with radiotherapy on three different gene expressions in lung adenocarcinoma A549 cell. mTOR gene, HIF-1α gene, Survivin gene were included in the gene group. Cell culture and RT-PCR were applied to finish this research. Hypoxia Control group, Hypoxia β-elemene group, Hypoxia β-elemene combined with irradiation group were set to compare the differences of three different gene expressions. The most active effects were found in the group of Hypoxia irradiation combined with β-elemene. In this group, the mTOR gene, HIF-1α gene, Survivin gene expressions were all down-regulated when compared with the single treatment groups, and there were significantly statistical differences.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Chemotherapy, Adjuvant; Curcuma; Down-Regulation; Gene Expression; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Phytotherapy; Plant Extracts; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes; Survivin; TOR Serine-Threonine Kinases

To investigate the effect of traditional Chinese medicine (TCM) on quality of life (QOF) and survival period in patients with progressive gastric cancer, and thus exploring its clinical efficacy.. TCM therapy applied in the 34 patients assigned in the TCM group (Group I ) included intravenous injection of Cinobufotalin, beta-elemene, or orally taking of anti-cancer Chinese herbs. The same TCM was also applied in the 36 of the combined treatment group (Group II), but in combined use of FOLFOX chemotherapeutic protocol. Twenty-one days was taken as one cycle and all the patients received 2 cycles of treatment.. The median survival period in group II was 31 months, while it was 30 months in group I; the 1-, 2-, 3-year survival rates in group II were 88.89%, 84.38% and 59.26%, and those in the group I were 82.35%, 71.43% and 65.00%, respectively with insignificant difference between the two groups (chi2 = 0.298, P > 0.05); QOF in group I was significantly superior to that in group II (P < 0.05), and the adverse reaction occurrence was significantly less in Group I than that in group II.. Chinese medicine treatment can improve the QOF and prolong the survival period of patients with progressive gastric cancer with few side effects.

Topics: Adenocarcinoma; Adult; Aged; Bufanolides; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Male; Medicine, Chinese Traditional; Middle Aged; Phytotherapy; Quality of Life; Retrospective Studies; Sesquiterpenes; Stomach Neoplasms; Survival Analysis; Survival Rate