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

Abstract

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.

Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells

“…To enlighten the molecular mechanisms of the cytotoxicity of UA ( Figure 1 A) on cancer cells, we first examined its ability to kill various types of cancer cells in culture by detecting plasma membrane-permeabilized cells using a membrane-impermeable propidium iodide (PI) dye. In agreement with previous reports [ 7 , 9 , 47 , 48 ], treatment with UA for 24 h induced death in human breast adenocarcinoma (MCF7) cells, osteosarcoma (U2OS) cells, cervical adenocarcinoma (HeLa) cells, and colorectal carcinoma (HCT116) cells in a dose-dependent manner, with lethal dose 50 (LD 50 ) values of 12.8 µM, 7.7 µM, 16.8 µM, and 19 µM, respectively ( Figure 1 B; Supplementary Figure S1B ). Even at a concentration of 8 μM that only killed ~5.5% of MCF7 cells in 24 h ( Figure 1 B), a treatment for 48 h reduced the total cell count of the MCF7 cells with >50% in comparison to the untreated or vehicle-treated cells ( Figure 1 B), suggesting that UA inhibited the cell proliferation.…”

Ursolic acid: biological functions and application in animal husbandry

“…In vitro experiments confirmed that 48 h of UA treatment (16 μM) could reduce the adhesion and infiltration of the human breast cancer adriamycin-resistant cell line MCF-7/ADR to human umbilical vein endothelial cells (HUVECs) and could also reduce migration in MCF-7/ADR cells ( 68 ). UA induced cellular DNA damage and initiated G0/G1 phase arrest in embryonic cancer cells, and could be a candidate for inhibiting the recurrence of cancer ( 70 ).…”

Ursolic acid: a natural modulator of signaling networks in different cancers

“…UA cause cell cycle arrest in ECSC increasing expression of P27 and P21 and decreasing expression of CDK4 and Cyclin D1 and it also cause apoptosis using BAX, Cytochrome C, BCL-xL, and BCL2 proteins. UA also increase the production of ROS that lead to DNA and cell damage [ 73 ].…”