Failure of current chemotherapeutic drugs leads to the recurrence of tumor pathology and mortality in lung cancer patients. This study aimed to evaluate the anticancer activity and related mechanisms of 4,5,4'-trihydroxy-3,3'-dimethoxybibenzyl (TDB), a bibenzyl extracted from Dendrobium ellipsophyllum Tang and Wang, in human lung cancer cells. Cytotoxicity of TDB (0-300 µM) in different types of human lung cancer cells (H460, H292 and H23) and human dermal papilla cells (DPCs) was evaluated via MTT viability assay. Selective anticancer activity of TDB against human lung cancer cells was demonstrated with a high IC (approximately > 300 µM) in DPCs, while IC in human lung cancer H460, H292 and H23 cells was approximately 100 ± 5.18, 100 ± 8.73 and 188.89 ± 8.30 µM, respectively. After treatment with 50 µM of TDB for 24 h, flow cytometry analysis revealed the significant increase of early and late apoptosis with absence of necrosis cell death in human lung cancer cells. The up-regulation of p53, a tumor-suppressor protein, was elucidated in human lung cancer cells treated with 10-50 µM of TDB. Alteration to down-stream signaling of p53 including activation of pro-apoptosis protein (Bcl-2-associated X protein; Bax), reduction of anti-apoptosis (B cell lymphoma 2; Bcl-2 and myeloid cell leukemia 1; Mcl-1) and suppression on protein kinase B (Akt) survival pathway were notified in TDB-treated lung cancer cells. The information obtained from this study strengthens the potential development of TDB as an anticancer compound with a favorable human safety profile and high efficacy.
Cancer stem-like cells (CSCs) are key mediators driving tumor initiation, metastasis, therapeutic failure, and subsequent cancer relapse. Thus, targeting CSCs has recently emerged as a potential strategy to improve chemotherapy. In this study, the anticancer activity and stemness-regulating capacity of 4,5,4′-trihydroxy-3,3′-dimethoxybibenzyl (TDB), a bibenzyl extracted from Dendrobium ellipsophyllum, are revealed in CSCs of various human lung cancer cells. Culture with TDB (5–10 μM) strongly abolished tumor-initiating cells in lung cancer H460, H23, and A549 cells in both anchorage-dependent and anchorage-independent colony formation assays. Through the 3D single-spheroid formation model, attenuation of self-renewal capacity was observed in CSC-enriched populations treated with 1–10 μM TDB for 7 days. Flow cytometry analysis confirmed the attenuation of %cell overexpressing CD133, a CSC biomarker, in TDB-treated lung cancer spheroids. TDB at 5–10 μM remarkably suppressed regulatory signals of p-Akt/Akt, p-GSK3β/GSK3β, and β-catenin corresponding to the downregulated mRNA level of stemness transcription factors including Nanog, Oct4, and Sox2. Moreover, the antiapoptosis Bcl-2 and Mcl-1 proteins, which are downstream molecules of Akt signaling, were evidently decreased in CSC-enriched spheroids after culture with TDB (1–10 μM) for 24 h. Interestingly, the diminution of Akt expression by specific siAkt effectively reversed suppressive activity of TDB targeting on the CSC phenotype in human lung cancer cells. These findings provide promising evidence of the inhibitory effect of TDB against lung CSCs via suppression of Akt/GSK3β/β-catenin cascade and related proteins, which would facilitate the development of this bibenzyl natural compound as a novel CSC-targeted therapeutic approach for lung cancer treatment.
Background: Winged bean or Psophocarpus tetragonolobus (WB) seeds have high protein content and could be applied as a source of antioxidant proteins and peptides. The utilization of gamma rays in plant protein extraction provides consumers with a safe and harmless technology.Objective: To determine the efficiency of gamma rays in the protein extraction process of WB seeds and investigate the antioxidant activity, cytotoxicity, cytoprotective effect of the gamma ray irradiated WB (WB-G) seed protein hydrolysate.Methods: WB seeds were irradiated with gamma ray (WB-G) and total protein were extracted by acid-base extraction method. The total protein was further hydrolyzed with alcalase enzyme to obtain the protein hydrolysate. The antioxidant activity was evaluated by DPPH and ABTS assay. The cytotoxicity and cytoprotective effect were determined by MTT assay. The cellular reactive oxygen species was further analyzed by ACFDA assay.Results: The protein extracted from WB-G seeds showed higher protein yield and antioxidant activity than that of non-irradiated seeds. After hydrolysis with alcalase enzyme at 55°C for 6 hours, WB-G protein hydrolysate with degree of hydrolysis of 90.00±0.91% exhibited strong antioxidant activity with IC50 value of 10.30±0.02 µg/ml and 3.10±0.06 µg/ml as measured by DPPH and ABTS assay, respectively. Moreover, it showed no toxicity toward L929 mouse fibroblast cells and IPEC-J2 cell lines and can reduce the damage caused by H2O2. As determined in cellular reactive oxygen species by H2-DCFDA assay, the WB-G protein hydrolysate can reduce the level of ROS and subsequently the damage of cell by H2O2. Conclusions: This study demonstrated that gamma ray irradiation on the WB seeds can increase the protein yield and its protein hydrolysate exhibited promising antioxidant activity and cytoprotective effect on cells against H2O2 damage. It might be developed as an alternative food or feed supplement.Keywords:Psophocarpus tetragonolobus; Gamma rays; Protein hydrolysate; Antioxidant activity; Cytoprotective effect
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