Reactive Oxygen Species-Mediated Autophagy by Ursolic Acid Inhibits Growth and Metastasis of Esophageal Cancer Cells

Lee, Na-Ri; Meng, Ruo Yu; Rah, So-Young; Jin, Hua; Ray, Navin; Kim, Seong-Hun; Park, Byung Hyun; Kim, Soo Mi

doi:10.3390/ijms21249409

Cited by 20 publications

(21 citation statements)

References 71 publications

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“…Numerous studies have reported that UA regulates the apoptosis, proliferation, metastasis, and cell cycle of different cancer cells through several signaling pathways, including Akt/PI3K [ 28 , 29 ], NF-Κβ [ 27 ], and STAT3 [ 26 , 78 ]. In agreement with those studies, our previous study showed that UA effectively inhibited cell viability and induced ROS-mediated autophagy in esophageal cancer cells through the Akt/mTOR signaling pathway [ 31 ], suggesting that UA might act as a potential anti-tumor reagent in esophageal cancer. Although PTX shows significant efficacy as a common esophageal cancer chemotherapy drug, chemo-resistance reduces its effects [ 44 , 45 ].…”

Section: Discussionsupporting

confidence: 88%

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Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade

Meng

Jin

Nguyen

et al. 2021

IJMS

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Ursolic acid (UA), a pentacyclic triterpenoid extracted from various plants, inhibits cell growth, metastasis, and tumorigenesis in various cancers. Chemotherapy resistance and the side effects of paclitaxel (PTX), a traditional chemotherapy reagent, have limited the curative effect of PTX in esophageal cancer. In this study, we investigate whether UA promotes the anti-tumor effect of PTX and explore the underlying mechanism of their combined effect in esophageal squamous cell carcinoma (ESCC). Combination treatment with UA and PTX inhibited cell proliferation and cell growth more effectively than either treatment alone by inducing more significant apoptosis, as indicated by increased sub-G1 phase distribution and protein levels of cleaved-PARP and cleaved caspase-9. Similar to the cell growth suppressive effect, the combination of UA and PTX significantly inhibited cell migration by targeting uPA, MMP-9, and E-cadherin in ESCC cells. In addition, combination treatment with UA and PTX significantly activated p-GSK-3β and suppressed the activation of Akt and FOXM1 in ESCC cells. Those effects were enhanced by the Akt inhibitor LY2940002 and inverted by the Akt agonist SC79. In an in vivo evaluation of a murine xenograft model of esophageal cancer, combination treatment with UA and PTX suppressed tumor growth significantly better than UA or PTX treatment alone. Thus, UA effectively potentiates the anti-tumor efficacy of PTX by targeting the Akt/FOXM1 cascade since combination treatment shows significantly more anti-tumor potential than PTX alone both in vitro and in vivo. Combination treatment with UA and PTX could be a new strategy for curing esophageal cancer patients.

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Section: Discussionsupporting

confidence: 88%

“…UA can prevent cancer through many signaling pathways, such as ROCK/PTEN, TGF-β1/ZEB1, and MAPK/ERK signaling [ 19 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. In addition, UA induces cell death with autophagy in patients with esophageal cancer [ 31 ]. Therefore, it seems necessary to study various functions of UA in cancer.…”

Section: Introductionmentioning

confidence: 99%

Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade

Meng

Jin

Nguyen

et al. 2021

IJMS

Self Cite

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“…(Castrejon-Jimenez et al, 2019). Similarly, UA is also reported to inhibit metastasis of esophageal cancer cells by ROS-mediated autophagy (Lee et al, 2020). Additionally, UA induces apoptosis and inhibits autophagy progression, leading to PC-12 cell death (Jung et al, 2018).…”

Section: Ursolic Acidmentioning

confidence: 96%

Targeting Autophagy with Natural Compounds in Cancer: A Renewed Perspective from Molecular Mechanisms to Targeted Therapy

et al. 2021

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Natural products are well-characterized to have pharmacological or biological activities that can be of therapeutic benefits for cancer therapy, which also provide an important source of inspiration for discovery of potential novel small-molecule drugs. In the past three decades, accumulating evidence has revealed that natural products can modulate a series of key autophagic signaling pathways and display therapeutic effects in different types of human cancers. In this review, we focus on summarizing some representative natural active compounds, mainly including curcumin, resveratrol, paclitaxel, Bufalin, and Ursolic acid that may ultimately trigger cancer cell death through the regulation of some key autophagic signaling pathways, such as RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, AMPK, ULK1, Beclin-1, Atg5 and p53. Taken together, these inspiring findings would shed light on exploiting more natural compounds as candidate small-molecule drugs, by targeting the crucial pathways of autophagy for the future cancer therapy.

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“…Analysis of data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases found that colon adenocarcinoma patients have increased expression of cyclin B1 that acts as a tumor promoting gene, and this overexpression can be reversed with treatment of ursolic acid in HCT-116 and SW-480 cells [107]. A number of other studies have demonstrated that ursolic acid has anti-cancer effects against various cancer types including esophageal cancer [108], pancreatic cancer [109], and colorectal cancer [110] via a number of different mechanisms, including the induction of ROS-mediated autophagy [108] and ER stressmediated RAGE inhibition, promoting apoptosis and autophagy [109], and up-regulation of ROS and caspase-3, -8, and -9, thereby inducing apoptosis [92]. Further anti-tumor effects of ursolic acid have been observed in papillary thyroid carcinoma cells, mediated via enhancement of fibronectin-1 expression and subsequent induction of apoptosis [111].…”

Section: Ursolic Acidmentioning

confidence: 99%

The Anti-Cancer Effects of Red-Pigmented Foods: Biomarker Modulation and Mechanisms Underlying Cancer Progression

2022

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Cancer is one the most malignant diseases that is a leading cause of death worldwide. Vegetables and fruits contain beneficial nutrients such as vitamins, minerals, folates, dietary fibers, and various natural bioactive compounds. These can prevent the pathological processes of many cancers and reduce cancer related mortality. Specifically, the anti-cancer effect of vegetables and fruits is largely attributable to the natural bioactive compounds present within them. A lot of bioactive compounds have very specific colors with pigments and the action of them in the human body varies by their color. Red-pigmented foods, such as apples, oranges, tomatoes, cherries, grapes, berries, and red wine, have been widely reported to elicit beneficial effects and have been investigated for their anti-tumor, anti-inflammatory, and antioxidative properties, as well as anti-cancer effect. Most of the anti-cancer effects of bioactive compounds in red-pigmented foods arise from the suppression of cancer cell invasion and metastasis, as well as the induction of apoptosis and cell cycle arrest. In this review, we assessed publications from the last 10 years and identified 10 bioactive compounds commonly studied in red-pigmented foods: lycopene, anthocyanin, β-carotene, pectin, betaine, rutin, ursolic acid, kaempferol, quercetin, and myricetin. We focused on the mechanisms and targets underlying the anti-cancer effect of the compounds and provided rationale for further investigation of the compounds to develop more potent anti-cancer treatment methods.

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Reactive Oxygen Species-Mediated Autophagy by Ursolic Acid Inhibits Growth and Metastasis of Esophageal Cancer Cells

Cited by 20 publications

References 71 publications

Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade

Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade

Targeting Autophagy with Natural Compounds in Cancer: A Renewed Perspective from Molecular Mechanisms to Targeted Therapy

The Anti-Cancer Effects of Red-Pigmented Foods: Biomarker Modulation and Mechanisms Underlying Cancer Progression

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