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Antiproliferative and palliative activity of flavonoids in colorectal cancer.
Fernández, J, Silván, B, Entrialgo-Cadierno, R, Villar, CJ, Capasso, R, Uranga, JA, Lombó, F, Abalo, R
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:112241
Abstract
Flavonoids are plant bioactive compounds of great interest in nutrition and pharmacology, due to their remarkable properties as antioxidant, anti-inflammatory, antibacterial, antifungal and antitumor drugs. More than 5000 different flavonoids exist in nature, with a huge structural diversity and a plethora of interesting pharmacological properties. In this work, five flavonoids were tested for their potential use as antitumor drugs against three CRC cell lines (HCT116, HT-29 and T84). These cell lines represent three different stages of this tumor, one of which is metastatic. Xanthohumol showed the best antitumor activity on the three cancer cell lines, even better than that of the clinical drug 5-fluorouracil (5-FU), although no synergistic effect was observed in the combination therapy with this drug. On the other hand, apigenin and luteolin displayed slightly lower antitumor activities on these cancer cell lines but showed a synergistic effect in combination with 5-FU in the case of HTC116, which is of potential clinical interest. Furthermore, a literature review highlighted that these flavonoids show very interesting palliative effects on clinical symptoms such as diarrhea, mucositis, neuropathic pain and others often associated with the chemotherapy treatment of CRC. Flavonoids could provide a double effect for the combination treatment, potentiating the antitumor effect of 5-FU, and simultaneously, preventing important side effects of 5-FU chemotherapy.
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Research on anti-hepatocellular carcinoma activity and mechanism of Polygala fallax Hemsl.
Yao, Z, Li, Y, Wang, Z, Lan, Y, Zeng, T, Gong, H, Zhu, K, Tang, H, Gu, S
Journal of ethnopharmacology. 2020;:113062
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Polygala fallax Hemsl. is a kind of traditional medicine of Yao Minority in China. In Chinese medicine practice, Polygala fallax Hemsl. is commonly prescribed to treat all kinds of acute and chronic hepatitis. AIM OF THE STUDY The present study aimed at investigating the effects and its possible mechanism of Polygala fallax Hemsl. on the proliferation and apoptosis of HepG2 cells (a kind of human hepatoma cell). MATERIALS AND METHODS Through a variety of experimental methods, including MTT technique and Hoechst staining to detect apoptosis in Hepatocyte HepG2 cells, flow cytometry to observe the pro-apoptotic and circulatory arrest effects as well as real-time fluorescence quantitative polymerase chain reaction (q-PCR) technique to examine the expression levels of Bcl-2/Bax gene and prote Western blot to examine the expression levels of bcl-2/bax,caspase3,8,9,CyclinA,p21,p27,ERK.Phospho-ERK and AKT, Phospho-AKT in HepG2 cells. RESULTS The results showed that compared with the control group, all polarity fractions of P. fallax had inhibitory effects on HepG2 cells, among which the inhibition effect of ethyl acetate fraction in 0.036 ± 0.001 mg/mL of IC50 for 24 h was the most obvious (P < 0.01). And the HepG2 cells induced at the ethyl acetate fraction could up-regulate Bax gene and protein, while down-regulating Bcl-2 gene and protein (P < 0.05) during S phase in a dose-dependent manner. In addition, the ethyl acetate site of Larch can also down regulate the expression of ERK, AKT and activate caspase 3, 8 and 9. CONCLUSION It could be concluded that the ethyl acetate fraction of Polygala fallax Hemsl. can significantly prohibit the proliferation of HepG2 cells. The possible mechanism is to promote the expression of Bax, inhibit the expression of Bcl-2, and down regulate the expression of AKT and ERK.
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Comparison of colony formation of human spermatogonial stem cells (SSCs) with and without collagen.
Shiva, R, Ghasem, S, Masoud, H, Sadat, KL, Ali, K, Reza, DM
JPMA. The Journal of the Pakistan Medical Association. 2016;(3):285-91
Abstract
OBJECTIVE To investigate the effects of collagen and growth factors on in vitro proliferation of human spermatogonial stem cells obtained from patients with non-obstructive azoospermia. METHODS The experimental cross-sectional study was conducted from February 2013 to April 2015 after obtaining approval from the ethics committee of Ahvaz Jundishapur University of Medical Sciences, Iran. Testicular sperm extractions of non-obstructive azoospermic patients were obtained from the Clinical Urology and Embryology, In Vitro Fertilization Department of Imam Khomeini Hospital. Spermatogonial stem cells and Sertoli cells, obtained from human testis biopsies by a two-step enzymatic digestion method, were purified using fluorescence- activated cell-sorting and daturastramonium-lectin, and were cultured separately. To investigate a more direct influential factor on colony formation, one control and two experimental groups were formed. Group 1 acted as the control in which spermatogonial stem cells were co-cultured with Sertoli cells alone. In group 2 they were co-cultured with Sertoli cells and growth factors such as leukaemia inhibitory factor, epidermal growth factor and glial cell-derived neurotrophic factor, and in group 3 with Sertoli cells along with growth factors in the presence of collagen-coated dishes. Number and diameter of the colonies were evaluated after 7 weeks. RESULTS Specimens obtained related to 21 patients. Number and diameter of the colonies in group 3 (18±2.6 and 276.6±45.5) were significantly more than both groups 1 (3.5±1 and D1:81.6±12) and group 2(11±2.2 and 165.2±32.5) (p<0.05 each). Also, the number and diameter of colony in group 2 were significantly better than the control group (p<0.05).Expression profile of the VASA, promyelocytic leukaemia zinc-finger (PLZF), Octamer-binding transcription factor 4 (OCT4) and integrin a6 (INTGa6) were detected in all groups. Based on cytochemical findings, OCT4 was expressed in the colonies of all three groups. CONCLUSIONS According to positive effects of collagen and growth factors on the colonisation of spermatogonial stem cells, it seems that using the cells may lead to better colonisation of this type of stem cells.
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In vitro anti cancer activity of ethanol extract fractions of Aerva lanata L.
Bhanot, A, Sharma, R, Singh, S, Noolvi, MN, Singh, S
Pakistan journal of biological sciences : PJBS. 2013;(22):1612-7
Abstract
To explore in vitro anticancer potential of Aerva lanata L. (flowering aerial part). The study was performed with 5 different human cell lines for the study of lung, leukaemia, prostate, colon and cervix cancer by using Sulphorhodamine B (SRB) assay. There were three doses of 10, 30 and 100 microg mL(-1) of each Aerva lanata L. Chloroform fraction (ALCF) and Aerva lanata L. Ethyl Acetate Fraction (ALEAF) used in this study. ALCF showed significant % inhibitory effect for leukaemia, lung and colon cancer at maximum concentration of 100 microg mL(-1) as compared to standard drug mitomycin. On the other hand ALEAF showed the significant % inhibitory effect for lung and cervix cancer at maximum concentration of 100 microg mL(-1) as compared to standard drug 5-fluoro Uracil (5-FU). From the above studies it is concluded that, the ethyl acetate fraction and chloroform fraction of Aerva lanata L. provide enough experimental evidence for anticancer activity and these fractions could be useful in medical care.
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Nutlin-3a, an MDM2 antagonist and p53 activator, helps to preserve the replicative potential of cancer cells treated with a genotoxic dose of resveratrol.
Zajkowicz, A, Krześniak, M, Matuszczyk, I, Głowala-Kosińska, M, Butkiewicz, D, Rusin, M
Molecular biology reports. 2013;(8):5013-26
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Abstract
Resveratrol is a natural compound that has been intensely studied due to its role in cancer prevention and potential as an anti-cancer therapy. Its effects include induction of apoptosis and senescence-like growth inhibition. Here, we report that two cancer cell lines (U-2 OS and A549) differ significantly in their molecular responses to resveratrol. Specifically, in U-2 OS cells, the activation of the p53 pathway is attenuated when compared to the activation in A549 cells. This attenuation is accompanied by a point mutation (458: CGA→TGA) in the PPM1D gene and overexpression of the encoded protein, which is a negative regulator of p53. Experimentally induced knockdown of PPM1D in U-2 OS cells resulted in slightly increased activation of the p53 pathway, most clearly visible as stronger phosphorylation of p53 Ser37. When treated with nutlin-3a, a non-genotoxic activator of p53, U-2 OS and A549 cells both responded with substantial activation of the p53 pathway. Nutlin-3a improved the clonogenic survival of both cell lines treated with resveratrol. This improvement was associated with lower activation of DNA-damage signaling (phosphorylation of ATM, CHK2, and histone H2AX) and higher accumulation of cells in the G1 phase of the cell cycle. Thus, the hyperactivation of p53 by nutlin-3a helps to preserve the replicative potential of cells exposed to resveratrol.
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Epicatechin gallate and catechin gallate are superior to epigallocatechin gallate in growth suppression and anti-inflammatory activities in pancreatic tumor cells.
Kürbitz, C, Heise, D, Redmer, T, Goumas, F, Arlt, A, Lemke, J, Rimbach, G, Kalthoff, H, Trauzold, A
Cancer science. 2011;(4):728-34
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Green tea catechins are considered as possible cancer preventive agents for several cancer types but little is known regarding their effects on pancreatic cancer cells. The best studied catechin and the major polyphenol present in green tea is epigallocatechin gallate (EGCG). In the present study, we investigated the in vitro anti-tumoral properties of EGCG on human pancreatic ductal adenocarcinoma (PDAC) cells PancTu-I, Panc1, Panc89 and BxPC3 in comparison with the effects of two minor components of green tea catechins, catechin gallate (CG) and epicatechin gallate (ECG). We found that all three catechins inhibited proliferation of PDAC cells in a dose- and time-dependent manner. Interestingly, CG and ECG exerted much stronger anti-proliferative effects than EGCG. Western blot analyses performed with PancTu-I cells revealed catechin-mediated modulation of cell cycle regulatory proteins (cyclins, cyclin-dependent kinases [CDK], CDK inhibitors). Again, these effects were clearly more pronounced in CG or ECG than in EGCG-treated cells. Importantly, catechins, in particular ECG, inhibited TNFα-induced activation of NF-κB and consequently secretion of pro-inflammatory and invasion promoting proteins like IL-8 and uPA. Overall, our data show that green tea catechins ECG and CG exhibit potent and much stronger anti-proliferative and anti-inflammatory activities on PDAC cells than the most studied catechin EGCG.
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Evaluation of a range of anti-proliferative assays for the preclinical screening of anti-psoriatic drugs: a comparison of colorimetric and fluorimetric assays with the thymidine incorporation assay.
George, SE, Anderson, RJ, Cunningham, A, Donaldson, M, Groundwater, PW
Assay and drug development technologies. 2010;(3):389-400
Abstract
Established treatments for psoriasis are generally based on antiproliferative, anti-inflammatory, or differentiation-modifying activity, or a combination of these effects. New agents for the treatment of psoriasis could be identified by high-throughput screening (HTS) of large compound libraries using keratinocyte proliferation models. Although several new proliferation assays have been developed, the radioactive [(3)H]-thymidine incorporation assay is still considered to be the gold standard for the evaluation of keratinocyte proliferation in vitro. In this study, we compare a number of simple, and reliable, colorimetric (MTT, NRU, SRB, and CVS), and fluorimetric (CAM and AB) methods with the [(3)H]-thymidine incorporation assay for the measurement of keratinocyte proliferation in the exponential growth phase in 96-well formats. The concentrations that induced 50% growth inhibition (GI(50)) were determined by each assay for the established antipsoriatics, dithranol, and methotrexate. Strong correlations were observed between the percentage growth inhibitions determined by the radioactive and the colorimetric assays, with no significant differences (P > 0.05) between their GI(50) values. The colorimetric assays are thus suitable alternatives to the radioactive assay for quantifying keratinocyte growth inhibition. We have also validated the use of the HaCaT cell line as a representative of the hyperproliferative psoriatic epidermis, in the preclinical screening of experimental anti-psoriatic agents.
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Impact of system L amino acid transporter 1 (LAT1) on proliferation of human ovarian cancer cells: a possible target for combination therapy with anti-proliferative aminopeptidase inhibitors.
Fan, X, Ross, DD, Arakawa, H, Ganapathy, V, Tamai, I, Nakanishi, T
Biochemical pharmacology. 2010;(6):811-8
Abstract
Amino acids activate nutrient signaling via the mammalian target of rapamycin (mTOR), we therefore evaluated the relationship between amino acid transporter gene expression and proliferation in human ovarian cancer cell lines. Expression of three cancer-associated amino acid transporter genes, LAT1, ASCT2 and SN2, was measured by qRT-PCR and Western blot. The effects of silencing the LAT1 gene and its inhibitor BCH on cell growth were evaluated by means of cell proliferation and colony formation assays. The system L amino acid transporter LAT1 was up-regulated in human ovarian cancer SKOV3, IGROV1, A2780, and OVCAR3 cells, compared to normal ovarian epithelial IOSE397 cells, whereas ASCT2 and SN2 were not. BCH reduced phosphorylation of p70S6K, a down-stream effector of mTOR, in SKOV3 and IGROV1 cells, and decreased their proliferation by 30% and 28%, respectively. Although proliferation of SKOV3 (S1) or IGROV1 (I10) cells was unaffected by LAT1-knockdown, plating efficiency in colony formation assays was significantly reduced in SKOV3(S1) and IGROV1(I10) cells to 21% and 52% of the respective plasmid transfected control cells, SKOV3(SC) and IGROV(IC), suggesting that LAT1 affects anchorage-independent cell proliferation. Finally, BCH caused 10.5- and 4.3-fold decrease in the IC(50) value of bestatin, an anti-proliferative aminopeptidase inhibitor, in IGROV1 and A2780 cells, respectively, suggesting that the combined therapy is synergistic. Our findings indicate that LAT1 expression is increased in human ovarian cancer cell lines; LAT1 may be a target for combination therapy with anti-proliferative aminopeptidase inhibitors to combat ovarian cancer.
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Statins inhibit the growth of variant human embryonic stem cells and cancer cells in vitro but not normal human embryonic stem cells.
Gauthaman, K, Manasi, N, Bongso, A
British journal of pharmacology. 2009;(6):962-73
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Abstract
BACKGROUND AND PURPOSE Statins inhibit proliferation of various human cancer cell lines in vitro. As human embryonic stem cells (hESCs) possess neoplastic-like properties we have evaluated the role of various statins on karyotypically normal hESCs (HES3 and BG01), abnormal hESCs (BG01V) and breast adenocarcinoma cells (MCF-7) to evaluate whether the mode of action of the statins was via a stemness pathway. EXPERIMENTAL APPROACH All cell lines were treated with simvastatin, pravastatin, lovastatin and mevastatin (1 micromol x L(-1) to 20 micromol x L(-1)) up to 7 days and their effects on cell proliferation, cell cycle, apoptosis and pluripotency studied. KEY RESULTS All four statins did not inhibit HES3 and BG01 proliferation, but BG01V and MCF-7 were inhibited by simvastatin, lovastatin and mevastatin. These inhibitory effects were reversed by the endogenous isoprenoids, farnesylpyrophosphate and geranylgeranylpyrophosphate. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling and cell cycle assay confirmed apoptosis in BG01V and MCF-7. Stem cell surface markers [stage-specific embryonic antigen-4, tumour rejection antigen-1-81, octamer-4 (OCT-4)] were expressed in HES3 and BG01, but not in BG01V cells, even after prolonged treatment with simvastatin. In BG01V and MCF-7, the pro-apoptotic Bcl-2-associated X protein genes were up-regulated, while the antiapoptotic BCL2 and SURVIVIN genes were down-regulated. Expression of the stemness-related genes namely, the growth differentiation factor-3, NANOG and OCT-4 was decreased in BG01V compared with BG01 and HES3. CONCLUSIONS AND IMPLICATIONS Normal hESCs were resistant to prolonged exposure to statins over a range of doses, compared with BG01V and MCF-7, probably because of genetic and behavioural differences. The statins not only have anti-cancer properties but can suppress abnormal hESCs thus promoting growth of normal hESCs in vitro.
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Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenström's macroglobulinemia.
Roccaro, AM, Leleu, X, Sacco, A, Moreau, AS, Hatjiharissi, E, Jia, X, Xu, L, Ciccarelli, B, Patterson, CJ, Ngo, HT, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2008;(6):1849-58
Abstract
PURPOSE Resveratrol (3,4',5-tri-hydroxy-trans-stilbene) is an antioxidant constituent of a wide variety of plant species including grapes. It has gained considerable attention because of its anticancer properties, as shown in solid and hematologic malignancies. Whether resveratrol could inhibit proliferation or induce cytotoxicity in Waldenström's macroglobulinemia (WM) was investigated. EXPERIMENTAL DESIGN We studied resveratrol-induced inhibition of proliferation and induction of cytotoxicity in WM cell lines, WM primary tumor cells, IgM-secreting cells, and peripheral blood mononuclear cells. The mechanisms of action and different signaling pathways involved were studied using Western blot and gene expression profile analysis. Resveratrol activity was also evaluated in the bone marrow microenvironment. We finally investigated whether or not resveratrol could have any synergistic effect if used in combination with other drugs widely used in the treatment of WM. RESULTS A schematic image illustrating the location and expression of the aurora kinases A, B, and C during mitosis. Resveratrol inhibited proliferation and induced cytotoxicity against WM cells, IgM-secreting cells, as well as primary WM cells, without affecting peripheral blood mononuclear cells; down-regulated Akt, extracellular signal-regulated kinase mitogen-activated protein kinases, and Wnt signaling pathways, as well as Akt activity; induced cell cycle arrest and apoptosis; and triggered c-Jun-NH(2)-terminal-kinase activation, followed by the activation of intrinsic and extrinsic caspase pathways. Lastly, adherence to bone marrow stromal cells did not confer protection to WM cells against resveratrol-induced cytotoxicity. Furthermore, resveratrol showed synergistic cytotoxicity when combined with dexamethasone, fludarabine, and bortezomib. CONCLUSION Our data show that resveratrol has significant antitumor activity in WM, providing the framework for clinical trials in this disease.