β-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2

Abstract

The inhibitors for EGF receptor tyrosine kinase (EGFR-TKIs) such as gefitinib have been used as a standard treatment for non-small cell lung cancer (NSCLC), but the increasingly occurrence of drug resistance, the associated adverse effects and the enrichment of cancer stem cells significantly impedes its clinical application. β-elemene is a natural sesquiterpene with potent anti-cancer ability, and also it is renowned for its plant-origin, safety and the additive effect with traditional therapies, which prompt us to explore its potential to co-operate with TKIs to achieve greater therapeutic efficacy. Impressively, our study demonstrates that, elemene, in combination of gefitinib, displayed a significantly higher activity in inhibiting lung cancer cellular proliferation, migration and invasion. More importantly, combinative treatment profoundly impaired the epithelial to mesenchymal transition (EMT), the stem-like properties and the self-renewal capacity of lung cancer cells, and hence impeded the in vivo tumor development. We also reveal that the synergistic anti-tumor effect of elemene and gefitinib was largely mediated their regulation of enhancer of zeste homolog 2 (EZH2), an oncogenic histone methyltransferase and gene transcriptional regulator. Thus, our data indicate that combinative treatment of elemene and gefitinib has greater anti-neoplastic activity and greater efficacies in targeting cancer stem-like properties, mainly through regulating the malignant gene modifier and hence the subsequent effector molecules required for cancer progression. The findings may have potential implications for treating aggressive and resistant lung cancers.

An ATF₂₄ peptide-functionalized β-elemene-nanostructured lipid carrier combined with cisplatin for bladder cancer treatment

“…The results showed that, compared with either single agent, the combination of ATF 24 -PEG-Lipo-β-E and DDP caused significant cell cycle arrest at the G2/M phase ( Figure 5F and 5I ). Consistent with this finding, the colony-forming ability of the KU-19-19 cells was significantly reduced by co-treatment of ATF 24 -PEG-Lipo-β-E and DDP, compared with those observed following treatment with either single agent treatment ( Figure 5G ) 46 . Together, the results indicated that the co-treatment of ATF 24 -PEG-Lipo-β-E and DDP had a synergistic effect in reducing cellular viability and proliferation in bladder cancer.…”

circSETD3 Contributes to Acquired Resistance to Gefitinib in Non-Small-Cell Lung Cancer by Targeting the miR-520h/ABCG2 Pathway

“…Considering that the epithelial-mesenchymal transition (EMT) and minor subpopulations of cancer stem cells (CSCs) have been reported to associated with acquired resistance of gefitinib in NSCLC, 23,24 we used qRT-PCR to study the effect of circSETD3 on the expression of EMT markers (vimentin, N-cadherin, E-cadherin, and keratin 18) and stemness-related markers (CD133, OCT4, NANOG, and SOX2). Our results showed that there were no significant differences in these markers after circSETD3-overexpression plasmid (OE-circSETD3) and circSETD3-short hairpin RNA (shRNA) (sh-circSETD3) (Figure S2), which indicates that the function of circSETD3 in gefitinib resistance was irrelevant with EMT or stem cell properties in NSCLC.…”

β‑elemene inhibits the generation of peritoneum effusion in pancreatic cancer via suppression of the HIF1A‑VEGFA pathway based on network pharmacology

“…β-elemene is a bioactive compound isolated from the traditional Chinese medicinal herb Curcuma wenyujin (38). It exerts a wide range of antitumor activities and has been approved in China to treat a wide spectrum of cancers including brain (9), breast (39), ovarian (40), gastric (41), hepatic (42) and lung cancers (43). A meta-analysis, including 46 clinical controlled trials with 2,992 patients, evaluated the efficacy and safety of β-elemene in treating malignant pleural effusion, and showed that β-elemene significantly improved the overall response rate in controlling malignant pleural effusion [risk ratio (RR) = 1.16; 95% CI: 1.08–1.23; P < 0.05) (14).…”