Bergapten induces G1 arrest and pro‐apoptotic cascade in colorectal cancer cells associating with p53/p21/PTEN axis

Lin, Chih Kuang; Lin, Chun‐Shiang; Lin, Hung‐Che; Li, Kuan-Te; Kao, Shao‐Hsuan; Tsao, Shih‐Ming

doi:10.1002/tox.22685

Cited by 22 publications

(26 citation statements)

References 35 publications

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“…Bergamottin induces apoptosis in human colon carcinoma cell line (RKO) and HT-29 cells by increasing caspase-3, 8, and 9; and PARP cleavage [61]. Bergapten inhibits breast cancer cell line (MCF-7) growth [62] and CRC cell viability [63] via inhibition of Akt. Bergaptol inducesMCF-7 cytotoxicity by the same mechanism [64].…”

Section: Pi3k/akt Inhibitionmentioning

confidence: 99%

“…p53 protein intervenes in two major apoptotic pathways: an “extrinsic pathway” induced by death receptors (TNF proteins such as DR4 and DR5) and an “intrinsic pathway” that regulates Family Bcl-2 proteins [ 5 ]. Bergapten (30 and 50 μM) decreased CRC (colorectal cancer) cells’ viability by apoptosis via upregulation of p53 , p21 , and PTEN [ 63 ]. Furanocoumarin A from Fructus liquidambaris induces the apoptosis in A549 by increasing p53 [ 79 ].…”

Section: Mechanistic Insightsmentioning

confidence: 99%

“…Bergapten (5-MOP) blocks G2/M phase in Hep-G2 with the inhibition of Cdk1 [ 91 ]. Bergapten (30 and 50 μM) instigated the G0/G1 and sub-G1 stage capture in CRC cells by a decrease of cyclin E/Cdk2 [ 63 ]. Bergaptol arrests G1-phase in MCF-7 [ 64 ]; Imperatorin in HT 29 and SGC-7901 cells [ 52 , 58 ] and isoimperatorin in DU145 and SGC-790 cells by increasing Cip1/p21 and Kip1/p27 expression and disrupting Cdk4 kinase synthesis [ 69 , 92 ].…”

Section: Mechanistic Insightsmentioning

confidence: 99%

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Anticancer Potential of Furanocoumarins: Mechanistic and Therapeutic Aspects

Ahmed

Khan

Aschner

et al. 2020

IJMS

128

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Cancer is one of the most extreme medical conditions in both developing and developed countries around the world, causing millions of deaths each year. Chemotherapy and/or radiotherapy are key for treatment approaches, but both have numerous adverse health effects. Furthermore, the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden of cancer overall requires novel efficacious treatment modalities. Natural medications offer feasible alternative options against malignancy in contrast to western medication. Furanocoumarins’ defensive and restorative impacts have been observed in leukemia, glioma, breast, lung, renal, liver, colon, cervical, ovarian, and prostate malignancies. Experimental findings have shown that furanocoumarins activate multiple signaling pathways, leading to apoptosis, autophagy, antioxidant, antimetastatic, and cell cycle arrest in malignant cells. Additionally, furanocoumarins have been shown to have chemo preventive and chemotherapeutic synergistic potential when used in combination with other anticancer drugs. Here, we address different pathways which are activated by furanocoumarins and their therapeutic efficacy in various tumors. Ideally, this review will trigger interest in furanocoumarins and their potential efficacy and safety as a cancer lessening agents.

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Section: Pi3k/akt Inhibitionmentioning

confidence: 99%

Section: Mechanistic Insightsmentioning

confidence: 99%

Section: Mechanistic Insightsmentioning

confidence: 99%

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Anticancer Potential of Furanocoumarins: Mechanistic and Therapeutic Aspects

Ahmed

Khan

Aschner

et al. 2020

IJMS

128

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“…p27Kip1 is a potential Cdk inhibitory tumor suppressor gene and p21Waf1 functions as an apoptosis-promoting protein [ 45 , 46 ]. In addition, the regulation of p21 is dependent and independent on the presence of functional p53, a transcriptional regulator that mediates cell cycle arrest following DNA damage [ 46 , 47 ]. In our cell model, MPP89 cells did not express p53, while Ist Mes1 and Ist Mes2 cells endowed p53, whose expression in the Ist Mes1 cell line was increased after treatment with exemestane or exemestane and rofecoxib combination.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel COX-2 / CYP19A1 axis involved in the mesothelioma pathogenesis opens new therapeutic opportunities

Nuvoli

Antoniani

Libener³

et al. 2021

J Exp Clin Cancer Res

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Background Based on previous studies highlighting that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of malignant pleural mesothelioma (MPM), and that aromatase (CYP19A1), an enzyme that plays a key role in estrogen biosynthesis, along with estradiol (E2) were expressed in MPM, this study aimed to investigate the possible interplay between COX-2 and CYP19A1 in the pathogenesis of mesothelioma, as well as the underlying mechanism. Methods The interaction between COX-2 and CYP19A1 was first investigated on different MPM lines upon PGE2, and COX-2 inhibitor (rofecoxib) treatment by western blot, RT-PCR. The key regulatory pathways involved in the COX-2 and CYP19A1 axis were further studied in MPM cells, after rofecoxib and exemestane (CYP19A1 inhibitor) treatment in monotherapy and in combination, by cell cycle distribution, western blot, and combination index analysis. To explore the role of COX-2/CYP19A1 axis in 3D preclinical models of MPM cells, we analyzed the effect of combination of COX-2 and CYP19A1 inhibitors in mesosphere formation. Immunohistochemical analysis of MPM mesosphere and specimens was utilized to evaluate the involvement of COX-2 on the CYP19A1 activity and the relationship between E2 and COX-2. Results PGE2 or rofecoxib treatment caused in MPM cells an increased or decreased, respectively, CYP19A1 expression at mRNA and protein levels. The effect of rofecoxib and exemestane combination in MPM cell proliferation was synergistic. Activation of caspase-3 and cleavage of PARP confirmed an apoptotic death for MPM cell lines. Increased expression levels of p53, p21, and p27, downregulation of cyclin D1 and inhibition of Akt activation (pAKT) were also found. The antagonistic effect of rofecoxib and exemestane combination found only in one cell line, was reverted by pretreatment with MK2206, a pAKT inhibitor, indicating pAKT as an actionable mediator in the COX-2-CYP19A1 axis. Reduction of size and sphere-forming efficiency in MPM spheres after treatment with both inhibitor and a decrease in COX-2 and E2 staining was found. Moreover, immunohistochemical analysis of 46 MPM samples showed a significant positive correlation between COX-2 and E2. Conclusions Collectively, the results highlighted a novel COX-2/CYP19A1 axis in the pathogenesis of MPM that can be pharmacologically targeted, consequently opening up new therapeutic options.

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“…5-Fluorouracil [5-FU; purity, >98%; ChemeGen (Shanghai) Biotechnology Co., Ltd.], which has been frequently used to treat advanced GC [ 13 ], was diluted to 5 μg/ml [ 14 ] for the determination of cell viability. TRAIL protein [purity, >95%; ACROBiosystems (Beijing) Biotechnology Co., Ltd., 100 ng/ml] [ 15 ] and pifithrin-α (p53 inhibitor; purity, >98%; Beyotime Institute of Biotechnology; 30 μg/ml) [ 16 ] were used to treat cells. Untreated cells were used as the control.…”

Section: Methodsmentioning

confidence: 99%

Cisatracurium besilate enhances the TRAIL-induced apoptosis of gastric cancer cells via p53 signaling

et al. 2021

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Cisatracurium besilate is the most commonly used non-depolarizing muscle relaxant in general anesthesia and in intensive care units. Studies have indicated that the proliferation of gastric cancer (GC) cells can be restrained by cisatracurium besilate. The present study aimed to investigate the mechanism underlying the role of cisatracurium besilate in TNF-related apoptosis-inducing ligand (TRAIL)-induced GC. The AGS cell line was exposed to cisatracurium besilate, and then cell viability, colony formation and apoptosis were assessed by performing Cell Counting Kit-8, colony formation, TUNEL and Western blot assays, respectively. Furthermore, the expression levels of p53 and p53 upregulated modulator of apoptosis (PUMA) were measured by Western blotting to determine the effect of cisatracurium besilate on p53/PUMA signaling. After co-treatment with p53 inhibitor, cisatracurium besilate and pifithrin-α/TRAIL, cell apoptosis was detected. Finally, cisatracurium besilate and pifithrin-α were used to co-treat TRAIL-induced AGS cells followed by apoptosis detection. Cisatracurium besilate treatment restrained the proliferation and promoted the apoptosis of AGS cells. Cisatracurium besilate also promoted the expression of p53 and PUMA in AGS cells. Furthermore, TRAIL induced the apoptosis of AGS cells, which was aggravated by cisatracurium besilate treatment. However, pifithrin-α reversed the synergistic effects of cisatracurium besilate and TRAIL on the activities of AGS cells. Therefore, the present study suggested that cisatracurium besilate enhanced the TRAIL-induced apoptosis of GC cells via p53 signaling, and the synergistic effects of cisatracurium besilate and TRAIL may achieve maximal therapeutic efficacy in GC management.

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Bergapten induces G1 arrest and pro‐apoptotic cascade in colorectal cancer cells associating with p53/p21/PTEN axis

Cited by 22 publications

References 35 publications

Anticancer Potential of Furanocoumarins: Mechanistic and Therapeutic Aspects

Anticancer Potential of Furanocoumarins: Mechanistic and Therapeutic Aspects

Identification of novel COX-2 / CYP19A1 axis involved in the mesothelioma pathogenesis opens new therapeutic opportunities

Cisatracurium besilate enhances the TRAIL-induced apoptosis of gastric cancer cells via p53 signaling

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