The anticancer activity of immune checkpoint inhibitors is attracting attention in various clinical sites. Since green tea catechin has cancer-preventive activity in humans, whether green tea catechin supports the role of immune checkpoint inhibitors was studied. We here report that (−)-epigallocatechin gallate (EGCG) inhibited programmed cell death ligand 1 (PD-L1) expression in non–small-cell lung cancer cells, induced by both interferon (IFN)-γ and epidermal growth factor (EGF). The mRNA and protein levels of IFN-γ–induced PD-L1 were reduced 40–80% after pretreatment with EGCG and green tea extract (GTE) in A549 cells, via inhibition of JAK2/STAT1 signaling. Similarly, EGF-induced PD-L1 expression was reduced about 37–50% in EGCG-pretreated Lu99 cells through inhibition of EGF receptor/Akt signaling. Furthermore, 0.3% GTE in drinking water reduced the average number of tumors per mouse from 4.1 ± 0.5 to 2.6 ± 0.4 and the percentage of PD-L1 positive cells from 9.6% to 2.9%, a decrease of 70%, in lung tumors of A/J mice given a single intraperitoneal injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In co-culture experiments using F10-OVA melanoma cells and tumor-specific CD3+ T cells, EGCG reduced PD-L1 mRNA expression about 30% in F10-OVA cells and restored interleukin-2 mRNA expression in tumor-specific CD3+ T cells. The results show that green tea catechin is an immune checkpoint inhibitor.
Summary Tocotrienols (T3s) and tocopherols (Tocs) are both members of the vitamin E family. It is known that d-tocotrienol (d-T3) has displayed the most potent anti-cancer activity amongst the tocotrienols. On the other hand, g-tocopherol (g-Toc) is reported to have a protective effect against prostate cancer. Therefore, we investigated whether the combination of g-Toc and d-T3 could strengthen the inhibitory effect of d-T3 on prostate cancer cell growth. In this study the effect of combined d-T3 (annatto T3 oil) and g-Toc (Tmix, g-Tocrich oil) therapy was assessed against human androgen-dependent prostate cancer cells (LNCaP). We found that combined treatment of d-T3 (10 mm) and g-Toc (5 mm) resulted in reinforced anti-prostate cancer activity. Specifically, cell cycle phase distribution analysis revealed that in addition to G1 arrest caused by the treatment with d-T3, the combination of d-T3 with g-Toc induced G2/M arrest. Enhanced induction of apoptosis by the combined treatment was also observed. These findings indicate that combination of d-T3 and g-Toc significantly inhibits prostate cancer cell growth due to the simultaneous cell cycle arrest in the G1 phase and G2/M phase.
Cancer stem cells (H1299-sdCSCs) were obtained from tumour spheres of H1299 human lung cancer cells. We studied low stiffness, a unique biophysical property of cancer cells, in H1299-sdCSCs and parental H1299. Atomic force microscopy revealed an average Young's modulus value of 1.52 kPa for H1299-sdCSCs, which showed low stiffness compared with that of H1299 cells, with a Young's modulus value of 2.24 kPa. (−)-Epigallocatechin gallate (EGCG) reversed the average Young's modulus value of H1299-sdCSCs to that of H1299 cells. EGCG treatment inhibited tumour sphere formation and ALDH1A1 and SNAI2 (Slug) expression. AXL receptor tyrosine kinase is highly expressed in H1299-sdcScs and AXL knockdown with siAXLs significantly reduced tumour sphere formation and ALDH1A1 and SNAI2 (Slug) expression. An AXL-high population of H1299-sdCSCs was similarly reduced by treatment with EGCG and siAXLs. Transplantation of an AXL-high clone isolated from H1299 cells into SCID/Beige mice induced faster development of bigger tumour than bulk H1299 cells, whereas transplantation of the AXL-low clone yielded no tumours. Oral administration of EGCG and green tea extract (GTE) inhibited tumour growth in mice and reduced p-AXL, ALDH1A1, and SLUG in tumours. Thus, EGCG inhibits the stemness and tumourigenicity of human lung cancer cells by inhibiting AXL. Green tea and (−)-epigallocatechin gallate (EGCG), the main constituent of green tea catechins, prevent cancer in humans, as demonstrated in phase II clinical trials, which showed that EGCG prevented colorectal adenoma recurrence and prostate cancer development from high-grade prostate intraepithelial neoplasia 1-4. Numerous investigators have reported therapeutic effects in various human cancer cell lines by combining EGCG and other green tea catechins with anticancer compounds, including anticancer drugs, nonsteroidal anti-inflammatory drugs, and phytochemicals 5,6. Because EGCG inhibits the expression of stemness marker genes and epithelialmesenchymal transition (EMT)-related genes in human cancer stem cells (CSCs) of the breast, lung, prostate and liver, CSCs are targets of EGCG for cancer prevention and therapy 7. Using atomic force microscopy (AFM), Gimzewski's laboratory first reported that metastatic cancer cells obtained from the pleural fluids of various cancer patients showed lower average Young's modulus values, indicating lower cell stiffness, than those of normal mesothelial cells from pleural effusion 8. Furthermore, they showed that treatment with green tea extract (GTE) increased the average Young's modulus values for metastatic cancer cells (i.e., reversed the values to those of normal cell stiffness levels) 9. Our previous study revealed that EGCG increased the stiffness of H1299 and Lu99 human non-small cell lung cancer (NSCLC) cells, inhibited the high expression of EMT-related proteins, such as vimentin and SLUG, and reduced cell motility 10. To investigate the inhibitory effects of EGCG on the biophysical properties of CSCs, we enriched CSCs from the tumour spheres of
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