Tannic Acid Inhibits Non-small Cell Lung Cancer (NSCLC) Stemness by Inducing G<sub>0</sub>/G<sub>1</sub> Cell Cycle Arrest and Intrinsic Apoptosis

Jang

et al. 2022

Journal of Oncology

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Embryonic cancer cells (CSCs) could cause different types of cancer, a skill that makes them even more dangerous than other cancer cells. Identifying CSCs using natural products is a good option as it inhibits the recurrence of cancer with moderate various effects. Ursolic acid (UA) is a pentacyclic triterpenoid extracted from fruit and herbal remedies and has known anticancer functions against various cancer cells. However, its potential against CSCs remains uncertain. This study was planned to examine the induction of cell apoptosis by the UA. For cell signaling studies, we performed experiments, which are real-time qPCR and immunoblotting. Also, various cellular processes were analyzed using flow cytometry. The results raised a barrier to cell proliferation by the UA in NTERA-2 and NCCIT cells. Morphological studies also confirmed the UA’s ability to cause cell death in embryonic CSCs. Examination of cell death importation showed that the UA formed the expression of the iNOS and thus the cell generation and mitochondrial reactive oxygen generation, which created a reaction to cellular DNA damage by raising the protein levels of phospho-histone ATR and ATM. In addition, the UA created the binding of the G0/G1 cell cycle to NTERA-2 and NCCIT cells, improved the expression levels of p21 and p27, and reduced the expression levels of CDK4, cyclin D1, and cyclin E, confirming the UA’s ability to initiate cell cycle arrest. Finally, the UA created an internal mechanism of apoptosis in the embryonic CSC using BAX and cytochrome c regulation as well as the regulation of BCL-xL and BCL-2 proteins. Therefore, UA could be the best candidate for targeting CSCs and thus suppressing the emergence of cancer.

Section: Introductionmentioning

confidence: 99%

Antitumor Effects of Natural Bioactive Ursolic Acid in Embryonic Cancer Stem Cells

Jang

et al. 2022

Journal of Oncology

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“…Mitochondria play a central role in the intrinsic pathway through the p53-dependent upregulation of BAX and downregulation of BCL-2, which promotes the release of cytochrome c from mitochondria to the cytosol. The presence of cytochrome c in the cytosol activates caspase proteins to induce apoptosis ( 44 , 45 ). Flow cytometry results suggested 6-gingerol induction of apoptosis in NCCIT and NTERA-2 cells.…”

Section: Discussionmentioning

confidence: 99%

Pivotal Role of Iron Homeostasis in the Induction of Mitochondrial Apoptosis by 6-Gingerol Through PTEN Regulated PD-L1 Expression in Embryonic Cancer Cells

et al. 2021

Front. Oncol.

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Embryonic cancer stem cells (CSCs) can differentiate into any cancer type. Targeting CSCs with natural compounds is a promising approach as it suppresses cancer recurrence with fewer adverse effects. 6-Gingerol is an active component of ginger, which exhibits well-known anti-cancer activities. This study determined the mechanistic aspects of cell death induction by 6-gingerol. To analyze cellular processes, we used Western blot and real-time qPCR for molecular signaling studies and conducted flow cytometry. Our results suggested an inhibition of CSC marker expression and Wnt/β-catenin signaling by 6-gingerol in NCCIT and NTERA-2 cells. 6-Gingerol induced reactive oxygen species generation, the DNA damage response, cell cycle arrest, and the intrinsic pathway of apoptosis in embryonic CSCs. Furthermore, 6-gingerol inhibited iron metabolism and induced PTEN, which both played vital roles in the induction of cell death. The activation of PTEN resulted in the inhibition of PD-L1 expression through PI3K/AKT/p53 signaling. The induction of PTEN also mediated the downregulation of microRNAs miR-20b, miR-21, and miR-130b to result in PD-L1 suppression by 6-gingerol. Hence, 6-gingerol may be a promising candidate to target CSCs by regulating PTEN-mediated PD-L1 expression.

“…The apoptosis pathway was divided into intrinsic and extrinsic pathways so that mitochondria can play a central role in the intrinsic pathway through p53-dependent upregulation of BAX and downregulation of BCL-2 to promote the release of cytochrome C from mitochondria to the cytosol to activate caspase proteins to proceed to apoptosis [ 44 , 45 ]. Flow cytometry results suggested the induction of apoptosis by MSM in NCCIT and NTERA-2 cells.…”

Section: Discussionmentioning

confidence: 99%

Iron Metabolism as a Potential Mechanism for Inducing TRAIL-Mediated Extrinsic Apoptosis Using Methylsulfonylmethane in Embryonic Cancer Stem Cells

et al. 2021

Cells

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Embryonic cancer stem cells (CSCs) can differentiate into any cancer type. Targeting CSC using natural compounds is a good approach as it suppresses cancer recurrence with fewer adverse effects, and methylsulfonylmethane (MSM) is a sulfur-containing compound with well-known anticancer activities. This study determined the mechanistic aspects of the anticancer activity of MSM. We used Western blotting and real-time qPCR for molecular signaling studies and conducted flow cytometry for analyzing the processes in cells. Our results suggested an inhibition in the expression of CSC markers and Wnt/β-catenin signaling. MSM induced TRAIL-mediated extrinsic apoptosis in NCCIT and NTERA-2 cells rather than an intrinsic pathway. Inhibition of iron metabolism-dependent reactive oxygen species (ROS) generation takes part in TRAIL-mediated apoptosis induction by MSM. Suppressing iron metabolism by MSM also regulated p38/p53/ERK signaling and microRNA expressions, such as upregulating miR-130a and downregulating miR-221 and miR-222, which resulted in TRAIL induction and thereby extrinsic pathway of apoptosis. Hence, MSM could be a good candidate for neoadjuvant therapy by targeting CSCs by inhibiting iron metabolism.