Amarogentin regulates self renewal pathways to restrict liver carcinogenesis in experimental mouse model

Sur, Subhayan; Pal, Debolina; Banerjee, Kaustav; Mandal, Suvra; Das, Ashes; Roy, Anup; Panda, Chinmay Kumar

doi:10.1002/mc.22356

Cited by 16 publications

(18 citation statements)

References 45 publications

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“…After washing with 1% ( v / v ) acetic acid, the bound dye was dissolved in 10‐mM trizma base and OD was measured at 510 nm using microplate reader (Techan Infinite M200, Mannedorf, Switzerland). The 50% inhibitory concentration (IC 50 ) was calculated as described by Sur et al () from the mean Optical density (OD) values obtained in triplicate independent experiments. For subsequent experiments, cells were treated with respective drugs at different doses (Table ).…”

Section: Methodsmentioning

confidence: 99%

Pongapin and Karanjin, furanoflavanoids of Pongamia pinnata, induce G2/M arrest and apoptosis in cervical cancer cells by differential reactive oxygen species modulation, DNA damage, and nuclear factor kappa‐light‐chain‐enhancer of activated B cell signaling

Roy

Pal

Sur

et al. 2019

Phytotherapy Research

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In this study, the antitumor activity of two furanoflavanoid derivatives, Pongapin and Karanjin, was evaluated in comparison with Plumbagin, a plant-derived polyphenol with proven antitumor activity. The compounds differentially inhibit the growth of different cancer cell lines (most effective on HeLa cells), with very low inhibitory effect on the growth of normal mouse embryonic fibroblast cell line. Pongapin like Plumbagin could significantly increase the intracellular reactive oxygen species (ROS) in the HeLa cells by stabilization of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (I-κB) expression and reduction of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression. In contrast, Karanjin could decrease ROS level by inhibition of I-κB degradation resulting restriction of NF-κB nuclear translocation. Pongapin and Plumbagin significantly increased DNA damage-induced p53 expression and p21 nuclear expression. However, Karanjin treatment showed low DNA damage with increased p53 expression. The compounds induced G2/M arrest and increase in SubG1 population, indicating induction of apoptosis. Apoptosis was further validated by acridine orange/ethidium bromide dual staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay in HeLa cells after treatment with the compounds. The compounds induced caspasedependent apoptosis through induction of Bax/Bcl-2 ratio either through increased expression of Bax by Pongapin and Plumbagin or low expression of Bcl-2 by Karanjin. Thus, Pongapin and Karanjin may be potential natural anticancer agents in the future, like Plumbagin. KEYWORDS Apoptosis, Karanjin, NF-κB, Plumbagin, Pongapin, reactive oxygen species Abbreviations: AO/EtBr, acridine orange/ethidium bromide; DCFH-DA, 2′-7′ dichlorofluorescin diacetate; FACS, fluorescence-activated cell sorting; IC 30 /IC 50 , concentration inhibiting cell viability by 30%/50%; ICC, immunocytochemistry; I-κB, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; OTM, olive tail moment; PBS, phosphate buffered saline; ROS, reactive oxygen species; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling.

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Section: Methodsmentioning

confidence: 99%

Pongapin and Karanjin, furanoflavanoids of Pongamia pinnata, induce G2/M arrest and apoptosis in cervical cancer cells by differential reactive oxygen species modulation, DNA damage, and nuclear factor kappa‐light‐chain‐enhancer of activated B cell signaling

Roy

Pal

Sur

et al. 2019

Phytotherapy Research

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“…Our previous study has verified that amarogentin prevents the malignant transformation of liver cancer cells through upregulation of p53 [ 12 ]. In addition, amarogentin has been reported to prevent liver carcinogenesis via regulating LCSC renewal [ 13 ]. Furthermore, p53 suppresses tumor proliferation by inhibiting the expression of CD133 [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Amarogentin Inhibits Liver Cancer Cell Angiogenesis after Insufficient Radiofrequency Ablation via Affecting Stemness and the p53-Dependent VEGFA/Dll4/Notch1 Pathway

Zhang

Wang

2020

BioMed Research International

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Background. Whether and how amarogentin suppresses the angiogenesis effect in liver cancer cells after insufficient radiofrequency ablation (iRFA) are still poorly studied. Methods. The number of liver cancer stem cells (LCSCs) and the level of vascular endothelial growth factor A (VEGFA) were assessed in liver cancer tissue after iRFA. Then, CD133-positive cells were detected in iRFA models of HepG2 and Huh7 cell lines treated with amarogentin. Tube formation assays were applied to observe the antiangiogenesis effects of amarogentin. In addition, the angiogenesis-related molecules p53, delta-like ligand 4 (Dll4), and Notch1 were detected in the iRFA cells and mouse models treated with amarogentin. Results. The mRNA and protein expression levels of CD133 and VEGFA were significantly higher in the residual liver cancer tissue than in the liver cancer tissues treated by hepatectomy. Amarogentin then markedly decreased the percentage of CD133-positive cells in the iRFA model in both HepG2 and Huh7 cell lines. The number of tubules formed by human umbilical vein endothelial cells (HUVECs) was significantly decreased by amarogentin. Inversely, the antiangiogenesis effect of amarogentin was counteracted after p53 silencing in the iRFA cell models. Conclusion. Amarogentin prevents the malignant transformation of liver cancer after iRFA via affecting stemness and the p53-dependent VEGFA/Dll4/Notch1 pathway to inhibit cancer cell angiogenesis.

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“…The effect of anthracycline antitumor antibiotics doxorubicin and nogalamycin on MCF‐7 and MDA MB 231 cell lines were analyzed by dye sulforhodamine B (SRB) to do the drug kinetics and the dose selection was done according to the standard protocol . Doxorubicin was purchased from Sigma‐Aldrich.…”

Section: Methodsmentioning

confidence: 99%

“…RNA extraction and qRT‐PCR analysis of MLH1/MSH2 genes were done as described above. For protein extraction and Western blot analysis MCF‐7 and MDA MB 231 cells were lysed by sonication with radioimmunoprecipitation assay buffer as described by Sur et al Proteins (80 µg) were separated by 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis and then transferred to polyvinylidinedifluoride membrane (Millipore, Burlington, MA). To reduce nonspecific binding, membranes were incubated with 3% nonfat dry milk for 1 to 2 hours at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Peak densities of the proteins of interest were normalized using peak density of loading control α‐tubulin. For immunocytochemistry, fluorescein isothiocyanate–conjugated secondary antibodies were used and 4′,6‐diamidino‐2‐phenylindole was used to stain the nucleus (Santa Cruz Biotechnology) . DNA was isolated for methylation analysis of MLH1/MSH2 promoters as described earlier.…”

Section: Methodsmentioning

confidence: 99%

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Hypomethylation of mismatch repair genes MLH1 and MSH2 is associated with chemotolerance of breast carcinoma: Clinical significance

Dasgupta

Islam

Alam

et al. 2018

Journal of Surgical Oncology

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Background and Objectives: The aim of the study was to understand the importance of mismatch repair genes MLH1 and MSH2 in chemotolerance and prognosis of breast carcinoma (BC). Methods: First, the alterations (deletion/methylation/expression) of MLH1 and MSH2 were analyzed in 45 neoadjuvant chemotherapy (NACT)-treated and 133 pretherapeutic BC samples. The chemotolerant BC cells were characterized by treating two BC cell lines MCF-7 and MDA MB 231 with two anthracycline antitumor antibiotics, doxorubicin and nogalamycin.Results: The deletion frequencies were 32% to 38% in MLH1/MSH2 genes and promoter methylation frequencies were 49% to 62% in MLH1 and 41% to 51% in MSH2 in both NACT-treated and pretherapeutic samples. The overall alteration of MLH1 and MSH2 was 58% to 71% in the samples. Reduced messenger RNA (mRNA) and protein expression were found in both the genes and it showed concordance with the molecular alterations. NACT-treated patients showed better prognosis. The chemotherapeutic drug induced increased mRNA/protein expression of the genes in BC cell lines was due to their promoter hypomethylation, as analyzed by quantitative methylation assay. This phenomenon was also evident in NACT-treated BC samples. Conclusion: MLH1/MSH2 genes play a critical role in the development of BC. Hypomethylation of MLH1/MSH2 genes might be important in chemotolerance of the disease. K E Y W O R D S breast carcinoma, doxorubicin/nogalamycin, MLH1/MSH2, neoadjuvant chemotherapy, promoter hypomethylation 1 | INTRODUCTION Breast carcinoma (BC) is the most common cancer among women worldwide. 1 It accounts for 25% of the cancer burden in Eastern Indian population. 2 Some of the etiological factors of BC are a genetic predisposition, exposure to ionization radiation, HPV infection, hormonal exposures, and obesity. 3-6 The early-onset BC (age of onset below 40 years) is more aggressive and shows lower survival rates compared J Surg Oncol. 2019;119:88-100. wileyonlinelibrary.com/journal/jso 88 | Abbreviations: 5-aza-dC, 5-aza-2′-deoxycytidine; BC, breast carcinoma; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HRP, horseradish peroxidase; MAI, microsatellite size alterations of one allele; MAII, microsatellite size alterations of two

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Amarogentin regulates self renewal pathways to restrict liver carcinogenesis in experimental mouse model

Cited by 16 publications

References 45 publications

Pongapin and Karanjin, furanoflavanoids of Pongamia pinnata, induce G2/M arrest and apoptosis in cervical cancer cells by differential reactive oxygen species modulation, DNA damage, and nuclear factor kappa‐light‐chain‐enhancer of activated B cell signaling

Pongapin and Karanjin, furanoflavanoids of Pongamia pinnata, induce G2/M arrest and apoptosis in cervical cancer cells by differential reactive oxygen species modulation, DNA damage, and nuclear factor kappa‐light‐chain‐enhancer of activated B cell signaling

Amarogentin Inhibits Liver Cancer Cell Angiogenesis after Insufficient Radiofrequency Ablation via Affecting Stemness and the p53-Dependent VEGFA/Dll4/Notch1 Pathway

Hypomethylation of mismatch repair genes MLH1 and MSH2 is associated with chemotolerance of breast carcinoma: Clinical significance

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