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Treatment of MCF-7 cells with 200 μM and 400 μM OLE for 24 h produced a notable decrease in cell viability.
|
[
{
"end": 18,
"label": "CellLine",
"start": 13,
"text": "MCF-7"
}
] |
ChemBL_V1
|
Specifically, at a concentration of 400 μM, OLE increased MCF-7 cell death by apoptosis induction .
|
[
{
"end": 63,
"label": "CellLine",
"start": 58,
"text": "MCF-7"
}
] |
ChemBL_V1
|
OLE effects might depend on the upregulation of p53 and Bax, and downregulation of Bcl-2, as demonstrated by incubating MCF-7 cells with 200 μM OLE for 48 h .
|
[
{
"end": 125,
"label": "CellLine",
"start": 120,
"text": "MCF-7"
}
] |
ChemBL_V1
|
Other studies using a very large concentration of OLE (600 μg/mL, ≈1100 μM) shed some light on a different mechanism ruling OLE-dependent induction of apoptosis.
|
[] |
ChemBL_V1
|
In fact, treatment of MCF-7 cells with the mentioned OLE concentration for 48 and 72 h reduced histone deacetylase 2 (HDAC2) and HDAC3 gene transcription in a time-dependent manner , and downregulated oncomiRs miR-21 and miR-155 .
|
[
{
"end": 27,
"label": "CellLine",
"start": 22,
"text": "MCF-7"
}
] |
ChemBL_V1
|
However, OLE-mediated effects on ER-positive cell viability may also be appreciated at lower doses.
|
[] |
ChemBL_V1
|
In fact, 30 μM and 50 μM OLE were able to reduce MCF-7 cell viability after 48 h, with no significant increase in the apoptotic rate .
|
[
{
"end": 54,
"label": "CellLine",
"start": 49,
"text": "MCF-7"
}
] |
ChemBL_V1
|
Moreover, 150 μM OLE reduced cell viability of ER-positive MCF-7 and T47D cells after 24 h .
|
[
{
"end": 64,
"label": "CellLine",
"start": 59,
"text": "MCF-7"
},
{
"end": 73,
"label": "CellLine",
"start": 69,
"text": "T47D"
}
] |
ChemBL_V1
|
Further experiments on MCF-7 cell line demonstrated a dose-dependent OLE-mediated antiproliferative effect on 17β-estradiol (E2)-induced cell growth when OLE concentration was used in the range of 10–75 μM. Instead, concentrations ≥ 100 μM were found to be toxic .
|
[
{
"end": 28,
"label": "CellLine",
"start": 23,
"text": "MCF-7"
}
] |
ChemBL_V1
|
As regards a possible anti-estrogenic action, 10 μM OLE had no effect on estrogen receptor α (ERα) basal activation, and 10–75 μM OLE had irrelevant activity on E2-induced ERα activation and E2-modulated ERα expression, but reduced E2-induced ERK1/2 phosphorylation .
|
[] |
ChemBL_V1
|
In ER-positive cells, invasiveness may be suppressed by OLE-mediated induction of autophagy.
|
[] |
ChemBL_V1
|
In fact, treatment of MCF-7 and T47D cell lines with 100 μM OLE reversed hepatocyte growth factor (HGF)- and 3-methyladenine (3-MA, an autophagy inhibitor)-induced migration, upregulating LC3II/LC3I and Beclin1, while downregulating p62 .
|
[
{
"end": 27,
"label": "CellLine",
"start": 22,
"text": "MCF-7"
},
{
"end": 36,
"label": "CellLine",
"start": 32,
"text": "T47D"
}
] |
ChemBL_V1
|
OLE was also able to reduce proliferation in triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 after 48 h incubation (IC50 = 500 μM), with RNA sequencing revealing alterations of the expression profile of genes involved in cell death, apoptosis, and response to stress .
|
[
{
"end": 96,
"label": "CellLine",
"start": 86,
"text": "MDA-MB-231"
},
{
"end": 111,
"label": "CellLine",
"start": 101,
"text": "MDA-MB-468"
}
] |
ChemBL_V1
|
Other reports documented that a dose as low as 50 μM was able to reduce MDA-MB-231 cell viability after 72 h incubation and IC50 = 36.2 μM was estimated for 72 h treatment .
|
[
{
"end": 82,
"label": "CellLine",
"start": 72,
"text": "MDA-MB-231"
}
] |
ChemBL_V1
|
A further attempt to deepen the mechanism of action in triple negative breast cancer showed that 12.5–100 μM OLE affected MDA-MB-231 cell viability in a dose- and time-dependent manner, reducing cellular migration and invasion capabilities, especially at doses ≥ 25 μM. OLE was able to induce dose-dependent apoptosis after 72 h incubation.
|
[
{
"end": 132,
"label": "CellLine",
"start": 122,
"text": "MDA-MB-231"
}
] |
ChemBL_V1
|
A deeper analysis, performed using a dose of 100 μM, revealed caspase-3/7 activation after 48 and 72 h, and a reduction in NF-κB phospho-p65 nuclear localization after 12 h .
|
[] |
ChemBL_V1
|
In a breast cancer cell line identified by the authors only by the letters “MDA”, 200 μg/mL OLE was able to interfere with the metastatic process, causing a time-dependent increase in mRNA levels of MMP inhibitors TIMP metallopeptidase inhibitor 1 (TIMP1) and TIMP3, while TIMP4 showed no further increase after 48 h incubation.
|
[
{
"end": 28,
"label": "CellLine",
"start": 5,
"text": "breast cancer cell line"
}
] |
ChemBL_V1
|
Simultaneously, the same concentration of OLE triggered a time-dependent decline in MMP2 and MMP9 mRNA levels .
|
[] |
ChemBL_V1
|
As regards HT activity in vivo, in a model of dimethylbenz[α]anthracene-induced mammary tumors in Sprague–Dawley rats treated with HT (0.5 mg/kg, 5 days/week for 6 weeks) reduced tumor growth, modulating the expression of genes involved in apoptosis and cell proliferation/survival .
|
[] |
ChemBL_V1
|
The relation between HT cytotoxic action in vitro and HER2 overexpression/hormone receptor status is less clear.
|
[] |
ChemBL_V1
|
Incubation of MCF-7 cell line with 50 μg/mL HT (≈324 μM) for 12 h was sufficient to trigger apoptosis , despite the fact that this result was not uniformly reproduced.
|
[
{
"end": 19,
"label": "CellLine",
"start": 14,
"text": "MCF-7"
}
] |
ChemBL_V1
|
In other experimental settings involving MCF-7 cells, the anti-proliferative activity of HT became evident at higher as well as even lower concentrations.
|
[
{
"end": 46,
"label": "CellLine",
"start": 41,
"text": "MCF-7"
}
] |
ChemBL_V1
|
HT used in the range of 5–400 μM for 16 h had no effect on MCF-7 cell proliferation; it became inhibited only at 600 μM .
|
[
{
"end": 64,
"label": "CellLine",
"start": 59,
"text": "MCF-7"
}
] |
ChemBL_V1
|
Another report documented a dose- and time-dependent effect of HT on MCF-7 cell viability, with 250 μM decreasing the percentage of viable cells after 72 h treatment, and 400 μM HT reducing cell viability as a consequence of 48 and 72 h incubation .
|
[
{
"end": 74,
"label": "CellLine",
"start": 69,
"text": "MCF-7"
}
] |
ChemBL_V1
|
However, at sub-lethal concentration (200 μM), HT had an impact on both (I) oxidative stress response, augmenting mRNA and protein levels of transcription factor nuclear respiratory factor 2 (Nrf2) and upregulating the transcription of its targets glutathione S-transferase alpha 2 (GSTA2) and heme oxigenase-1 (HO-1), and (II) energy homeostasis, reducing mRNA level of mitochondria biogenesis regulator PPARγ coactivator-1α (PGC-1α), while increasing its protein level and downregulating expression (in terms of mRNA) of mitochondrial function regulators estrogen-related receptor α (ERRα) and deacetylase sirtuin 3 (SIRT3) .
|
[] |
ChemBL_V1
|
Other research records showed that a reduction in ER-positive cell viability may be obtained even at lower HT doses, as demonstrated by 72 h treatment with 50 μM and 100 μM HT, which significantly diminished the percentage of viable MCF-7 cells , and by 100 μM and 150 μM HT-induced reduction in MCF-7 and T47D cell viability after 24 h .
|
[
{
"end": 238,
"label": "CellLine",
"start": 233,
"text": "MCF-7"
},
{
"end": 301,
"label": "CellLine",
"start": 296,
"text": "MCF-7"
},
{
"end": 310,
"label": "CellLine",
"start": 306,
"text": "T47D"
}
] |
ChemBL_V1
|
Incubating MCF-7 cells with 10–75 μM HT showed an inhibitory effect on E2-induced cell growth, with HT becoming toxic at concentrations ≥ 100 μM. ERα basal activation was induced by 10 μM HT, but (similarly to OLE) when HT was used at concentrations of 10–75 μM, it exhibited no effect on E2-induced ERα activation and E2-modulated ERα expression, while reducing levels of phospho-ERK1/2 (pERK1/2) .
|
[
{
"end": 16,
"label": "CellLine",
"start": 11,
"text": "MCF-7"
}
] |
ChemBL_V1
|
As regards invasiveness of ER-positive cells, experimental evidence obtained in MCF-7 and T47D cells confirmed that 50 μM HT elicited effects similar to those recorded for OLE on HGF- and 3-MA-induced cell migration .
|
[
{
"end": 85,
"label": "CellLine",
"start": 80,
"text": "MCF-7"
},
{
"end": 94,
"label": "CellLine",
"start": 90,
"text": "T47D"
}
] |
ChemBL_V1
|
In human triple negative breast cancer cells MDA-MB-231, HT seemed to lose effectiveness with respect to time, with IC50 values changing from 107.17 μM to 183.65 μM in 72 h .
|
[
{
"end": 55,
"label": "CellLine",
"start": 45,
"text": "MDA-MB-231"
}
] |
ChemBL_V1
|
For the same cell line, higher IC50 values (230 μM) were reported for 72 h treatment .
|
[] |
ChemBL_V1
|
On the contrary, another study demonstrated that 100 μM HT promoted MDA-MB-231 cell viability during the first 24 h, becoming ineffective after 48 and 72 h, whereas 250 μM HT became able to reduce cell viability after 72 h treatment, and 400 μM HT significantly diminished cell viability at all the three assayed time points (24, 48, and 72 h) .
|
[
{
"end": 78,
"label": "CellLine",
"start": 68,
"text": "MDA-MB-231"
}
] |
ChemBL_V1
|
This piece of data is openly conflicting with reports documenting a loss of MDA-MB-231 viability after 72 h incubation at all tested HT doses (10–100 μM) .
|
[
{
"end": 86,
"label": "CellLine",
"start": 76,
"text": "MDA-MB-231"
}
] |
ChemBL_V1
|
The reduction in triple negative breast cell viability may depend on HT acting as a copper chelator, thus perturbating copper homeostasis, as demonstrated in MDA-MB-231 cells by 100 μM HT-mediated increase in the copper chaperone for superoxide dismutase (CCS) after 48 h, and reduction in the subunit II of the complex IV of the mitochondrial respiratory chain cytochrome c oxidase (CcO) after 72 h. Also, HT altered epithelial and mesenchymal markers, and reduced MDA-MB-231 aggressiveness and migration by diminishing copper-dependent Akt phosphorylation.
|
[
{
"end": 168,
"label": "CellLine",
"start": 158,
"text": "MDA-MB-231"
},
{
"end": 476,
"label": "CellLine",
"start": 466,
"text": "MDA-MB-231"
}
] |
ChemBL_V1
|
Similar conclusions were drawn for MDA-MB-468 cells .
|
[
{
"end": 45,
"label": "CellLine",
"start": 35,
"text": "MDA-MB-468"
}
] |
ChemBL_V1
|
Other triple negative breast cancer cell lines were identified as particularly resistant towards HT-mediated cytotoxicity, e.g., SUM159 (IC50 = 300 μM) .
|
[] |
ChemBL_V1
|
In naturally HER2-overexpressing human breast cancer cells SKBR3, HT concentrations up to 100 μM failed to elicit a cytotoxic response after 5 days, and only weakly interfered with cell proliferation, but reduced HER2 protein expression after 48 h. However, in engineered HER2-overexpressing MCF-7 cells, 100 μM HT efficaciously triggered apoptosis, diminished cell proliferation, and downregulated HER2 .
|
[
{
"end": 64,
"label": "CellLine",
"start": 59,
"text": "SKBR3"
},
{
"end": 297,
"label": "CellLine",
"start": 292,
"text": "MCF-7"
}
] |
ChemBL_V1
|
Other authors suggest that in vitro cytotoxic action of OLE and HT may depend on cell density in culture, hypoxia, and ROS homeostasis.
|
[] |
ChemBL_V1
|
Han et al. observed that incubation with 200 μg/mL OLE and 50 μg/mL HT for 12 h exhibited the most efficient inhibition of cell growth when MCF-7 seeded cell number did not exceed 2 × 10 cell/well in a 96-well plate .
|
[
{
"end": 145,
"label": "CellLine",
"start": 140,
"text": "MCF-7"
}
] |
ChemBL_V1
|
Hypoxia increased HT cytotoxicity in MCF-7 cell line, an effect that became evident at 400 μM (vs. 600 μM in normoxic conditions).
|
[
{
"end": 42,
"label": "CellLine",
"start": 37,
"text": "MCF-7"
}
] |
ChemBL_V1
|
In hypoxic conditions, 200 μM HT was also able to exert the same actions on oxidative stress response and energy homeostasis as those reported above for normoxic MCF-7 cells .
|
[
{
"end": 167,
"label": "CellLine",
"start": 162,
"text": "MCF-7"
}
] |
ChemBL_V1
|
Moreover, in hypoxic MCF-7 cells, 75–200 μM HT reduced the amount of PARP-1, a DNA-binding protein involved in oxidative stress response, but inhibition of PARP-1 activity was achieved only with 200 μM HT .
|
[
{
"end": 26,
"label": "CellLine",
"start": 21,
"text": "MCF-7"
}
] |
ChemBL_V1
|
The same concentration of HT accounted for the reduction in the phosphorylated form of kinase mammalian target of rapamycin (mTOR), which in turn produced a reduction in hypoxia inducible factor-1α (HIF-1α), one of the two subunits of the heterodimeric transcription factor HIF-1, ruling the cellular response to hypoxia .
|
[] |
ChemBL_V1
|
More importantly, 200 μM HT upregulated the transcription of angiogenic factors adrenomedullin (AM) and VEGF with an HIF-1α-independent mechanism .
|
[] |
ChemBL_V1
|
Treatment of MDA-MB-231 cells with 200 μg/mL olive leaf extract containing 87% OLE for 24 h induced S phase cell cycle arrest and apoptosis by a mechanism that was strongly dependent on OLE-mediated ROS accumulation and downregulation of protein expression of catalase (CAT) and SOD2 .
|
[
{
"end": 23,
"label": "CellLine",
"start": 13,
"text": "MDA-MB-231"
}
] |
ChemBL_V1
|
Treatment of MCF-7 cells and another breast cancer cell line generically indicated by the authors simply as “MDA” with 25–100 μM HT for 72 h reduced cell viability in a dose-dependent fashion (mean IC50 ± S.D. = 52 ± 4 μM for of MDA and 58 ± 8 μM for MCF-7), mainly in culture conditions favoring H2O2 accumulation .
|
[
{
"end": 18,
"label": "CellLine",
"start": 13,
"text": "MCF-7"
},
{
"end": 60,
"label": "CellLine",
"start": 37,
"text": "breast cancer cell line"
},
{
"end": 112,
"label": "CellLine",
"start": 109,
"text": "MDA"
},
{
"end": 232,
"label": "CellLine",
"start": 229,
"text": "MDA"
},
{
"end": 256,
"label": "CellLine",
"start": 251,
"text": "MCF-7"
}
] |
ChemBL_V1
|
HT may also have a role in changing the tumor microenvironment.
|
[] |
ChemBL_V1
|
Aged quiescent normal human fibroblasts were able to stimulate MDA-MB-231 proliferation by synthetizing and secreting large amounts of chemokine C-C motif ligand 5 (CCL5), which in turn activated pro-proliferative ERK1/2 and cyclin D1 signalling pattern.
|
[
{
"end": 73,
"label": "CellLine",
"start": 63,
"text": "MDA-MB-231"
}
] |
ChemBL_V1
|
Treatment of 100 μM and 200 μM HT prevented CCL5 accumulation in aged quiescent normal human fibroblasts, limiting the proliferation of MDA-MB-231 cells.
|
[
{
"end": 146,
"label": "CellLine",
"start": 136,
"text": "MDA-MB-231"
}
] |
ChemBL_V1
|
A similar growth inhibition was also obtained for MCF-7 cells .
|
[
{
"end": 55,
"label": "CellLine",
"start": 50,
"text": "MCF-7"
}
] |
ChemBL_V1
|
Hepatocellular carcinoma (HCC) or hepatoma is the most frequent primary liver tumor and the sixth most common cancer worldwide, with a very modest survival rate and a complex management .
|
[] |
ChemBL_V1
|
Results on OLE-mediated effects on hepatoma cells are conflicting.
|
[] |
ChemBL_V1
|
In vitro, 20–80 μM OLE reduced hepatoma Huh7 and HepG2 cell line viability in a dose-dependent manner in 24 h .
|
[
{
"end": 44,
"label": "CellLine",
"start": 40,
"text": "Huh7"
},
{
"end": 54,
"label": "CellLine",
"start": 49,
"text": "HepG2"
}
] |
ChemBL_V1
|
As determined in HepG2 cells, OLE effects on cell viability are linked to apoptosis induction, mediated by an increase in Bax and cleaved (i.e., activated) caspase-9, caspase-8, caspase-3, and PARP-1 levels, and a decrease in phospho-Akt and Bcl-2 protein levels.
|
[
{
"end": 22,
"label": "CellLine",
"start": 17,
"text": "HepG2"
}
] |
ChemBL_V1
|
After treating HepG2 cells with 50 μM OLE for 24 h, the measured reduction in cell viability seemed related to OLE-mediated accumulation of ROS .
|
[
{
"end": 20,
"label": "CellLine",
"start": 15,
"text": "HepG2"
}
] |
ChemBL_V1
|
However, one report documented the absence of effects on cell viability after treating HepG2 cells with 10–10 M OLE for 24 h , and another study described no effect on HepG2 cell viability after 48 h incubation with 15–200 μM OLE .
|
[
{
"end": 92,
"label": "CellLine",
"start": 87,
"text": "HepG2"
},
{
"end": 173,
"label": "CellLine",
"start": 168,
"text": "HepG2"
}
] |
ChemBL_V1
|
The dose-dependent cytotoxic effect of HT on HCC was demonstrated in human hepatoma HepG2 and Hep3B cell lines, with a time-dependent increase in effectiveness.
|
[
{
"end": 89,
"label": "CellLine",
"start": 84,
"text": "HepG2"
},
{
"end": 99,
"label": "CellLine",
"start": 94,
"text": "Hep3B"
}
] |
ChemBL_V1
|
In fact, 80–200 μM HT significantly affected cell metabolic activity after 48 h, whereas a concentration as low as 30 μM was sufficient to reduce the percentage of viable cells in both cell lines after 72 h of incubation .
|
[] |
ChemBL_V1
|
These effects might rely on inhibition of lipogenesis.
|
[] |
ChemBL_V1
|
In fact, in both cell lines’ fatty acid synthase (FASN) activity was consistently inhibited by 200 μM HT (with significant enzymatic inhibition starting with 30 μM and 80 μM HT for HepG2 and Hep3B, respectively), whereas farnesyl diphosphate synthase (FPPS) lipogenic enzyme activity was inhibited only in HepG2 cells .
|
[
{
"end": 186,
"label": "CellLine",
"start": 181,
"text": "HepG2"
},
{
"end": 196,
"label": "CellLine",
"start": 191,
"text": "Hep3B"
},
{
"end": 311,
"label": "CellLine",
"start": 306,
"text": "HepG2"
}
] |
ChemBL_V1
|
A further report confirmed the dose- and time-dependent inhibition of cell viability of human HCC cell lines HepG2, Hep3B, and Huh-7, and ascitic fluid-derived cell line SK-HEP-1 for HT doses up to 400 μM, with G2/M cell cycle arrest and inactivation of cell growth-promoting Akt and NF-κB pathways .
|
[
{
"end": 114,
"label": "CellLine",
"start": 109,
"text": "HepG2"
},
{
"end": 121,
"label": "CellLine",
"start": 116,
"text": "Hep3B"
},
{
"end": 132,
"label": "CellLine",
"start": 127,
"text": "Huh-7"
},
{
"end": 178,
"label": "CellLine",
"start": 170,
"text": "SK-HEP-1"
}
] |
ChemBL_V1
|
Instead, the role of redox homeostasis in HT-dependent cytotoxicity is less clear in the context of HCC.
|
[] |
ChemBL_V1
|
Cell antioxidant capacities were promoted by 48 h treatment with 80–200 μM HT in HepG2 cells; on the contrary, the same effect was elicited by only 48 h treatment with 30 μM HT in Hep3B cells .
|
[
{
"end": 86,
"label": "CellLine",
"start": 81,
"text": "HepG2"
},
{
"end": 185,
"label": "CellLine",
"start": 180,
"text": "Hep3B"
}
] |
ChemBL_V1
|
However, HT triggers other molecular mechanisms that may influence HCC cell behavior besides affecting cell viability, at least in vitro.
|
[] |
ChemBL_V1
|
Treatment of human hepatoma HepG2 cells with 50–200 μM HT determined an increase in intracellular ionized calcium levels ([Ca]i) with the contribution of both Ca influxes and mobilization of endoplasmic reticulum depots.
|
[
{
"end": 33,
"label": "CellLine",
"start": 28,
"text": "HepG2"
}
] |
ChemBL_V1
|
Anyway, Ca dynamics seemed to be unrelated to HT-dependent reduction in cell viability , but they might be implicated in changes in the cell secretome , although definitive proofs are still missing.
|
[] |
ChemBL_V1
|
Cholangiocarcinoma is the term used to identify rare heterogeneous cancers arising in intrahepatic and extrahepatic bile ducts .
|
[] |
ChemBL_V1
|
Instead, gallbladder cancer is the most common biliary tract cancer, characterized by a very unfavorable prognosis .
|
[] |
ChemBL_V1
|
Treatment of cholangiocarcinoma cell line KMBC and TFK-1, and gallbladder carcinoma GBC-SD cells with 25–200 μM HT for 24, 48, and 72 h reduced cell proliferation in a time- and dose-dependent manner.
|
[
{
"end": 46,
"label": "CellLine",
"start": 42,
"text": "KMBC"
},
{
"end": 56,
"label": "CellLine",
"start": 51,
"text": "TFK-1"
},
{
"end": 90,
"label": "CellLine",
"start": 84,
"text": "GBC-SD"
}
] |
ChemBL_V1
|
A time- (24–72 h) and dose (75–150 μM)-dependent reduction in ERK1/2 phosphorylation was detected in all the three mentioned cell lines.
|
[] |
ChemBL_V1
|
The 72 h incubation of KMBC, TFK-1, and GBC-SD cells with 75 μM and 150 μM HT caused G2/M phase cell cycle arrest, induced apoptosis, augmented the levels of cleaved PARP, Bax, cleaved caspase-3, and cleaved caspase-9, and reduced Bcl-2 levels.
|
[
{
"end": 27,
"label": "CellLine",
"start": 23,
"text": "KMBC"
},
{
"end": 34,
"label": "CellLine",
"start": 29,
"text": "TFK-1"
},
{
"end": 46,
"label": "CellLine",
"start": 40,
"text": "GBC-SD"
}
] |
ChemBL_V1
|
Also, treatment of TFK-1 cell xenograft tumor grown in nude BALB/c mice with peritoneal injection of 500 mg/kg/day HT for 3 weeks reduced tumor growth in vivo .
|
[
{
"end": 24,
"label": "CellLine",
"start": 19,
"text": "TFK-1"
},
{
"end": 66,
"label": "CellLine",
"start": 60,
"text": "BALB/c"
}
] |
ChemBL_V1
|
Colorectal cancer, including tumors of the colon and/or rectum, is the third most common cancer and the second most common cancer-related cause of death worldwide.
|
[] |
ChemBL_V1
|
It is characterized by high rates of acquired multidrug resistance, leading to chemotherapy failure, relapse, and development of lethal disease .
|
[] |
ChemBL_V1
|
The classical Dukes’ classification distinguishes between “type A” and “type B” tumors, according to the absence or presence of tumor infiltration in extra-rectal tissues, respectively, and designates as “type C” those tumors with regional lymph node metastasis, and as “type C1” and “type C2” those malignancies exhibiting involvement of more distant lymph nodes .
|
[] |
ChemBL_V1
|
In an in vivo model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colorectal cancer in C57BL/6 mice, 50 and 100 mg/kg OLE reduced the incidence of colonic neoplasms, and levels of proliferation regulators NF-κB subunit p65, phosphorylated form of signal transducer and activator of transcription 3 (STAT3), and phospho-Akt, while increasing Bax protein expression.
|
[
{
"end": 107,
"label": "CellLine",
"start": 100,
"text": "C57BL/6"
}
] |
ChemBL_V1
|
In addition, 100 mg/kg OLE reduced cell proliferation (as confirmed by reduced expression of proliferation marker Ki67) .
|
[] |
ChemBL_V1
|
Colorectal carcinoma cell lines may exhibit different sensitivity towards OLE-mediated effects on cell growth.
|
[] |
ChemBL_V1
|
In fact, treatment of colon carcinoma RKO cell line with 20–80 μM OLE diminished cell viability in a dose-dependent fashion .
|
[
{
"end": 41,
"label": "CellLine",
"start": 38,
"text": "RKO"
}
] |
ChemBL_V1
|
Similarly, 10–100 μM OLE reduced viability of Dukes’ type C colorectal adenocarcinoma SW620 cell line after 72 h incubation, becoming able to increase the rate of apoptosis at the highest concentration tested .
|
[
{
"end": 91,
"label": "CellLine",
"start": 86,
"text": "SW620"
}
] |
ChemBL_V1
|
On the contrary, 10–50 μM OLE had no effect on the viability of colon adenocarcinoma HT29 cell line, but induced apoptosis only at a concentration of 100 μM .
|
[
{
"end": 89,
"label": "CellLine",
"start": 85,
"text": "HT29"
}
] |
ChemBL_V1
|
Incubation with 400 μM and 800 μM OLE reduced HT-29 cell viability at all three tested time points (24, 48, and 72 h), inducing G0/G1 phase cell cycle arrest after 24 h treatment.
|
[
{
"end": 51,
"label": "CellLine",
"start": 46,
"text": "HT-29"
}
] |
ChemBL_V1
|
However, only 800 μM OLE was able to promote apoptosis in HT-29 cells after 24 h incubation .
|
[
{
"end": 63,
"label": "CellLine",
"start": 58,
"text": "HT-29"
}
] |
ChemBL_V1
|
Treatment with 400 μM and 800 μM OLE produced a reduction in protein expression of HIF-1α, which was detected after 2 h and persisted up to 48 h. Instead, p53 protein expression was increased only by 48 h incubation with 800 μM OLE .
|
[] |
ChemBL_V1
|
In vitro, the effects of low or nutritionally relevant HT doses are poorly explored, and HT is suspected to interfere with colorectal cancer insurgence acting as a methylation pattern modifying agent.
|
[] |
ChemBL_V1
|
In fact, incubation of human colorectal adenocarcinoma Caco2 cell line with 10 μM HT increased DNA methylation, leading to the repression of the crucial colorectal cancer promoter endothelin receptor type A (EDNRA) .
|
[
{
"end": 60,
"label": "CellLine",
"start": 55,
"text": "Caco2"
}
] |
ChemBL_V1
|
Experimental evidence supports a pro-oxidant action of low doses of HT in colorectal cancer cells.
|
[] |
ChemBL_V1
|
Treatment of human colorectal carcinoma HCT116 cells and human Dukes’ type C colorectal adenocarcinoma SW620 cells with 5–20 μM HT for 24 h determined a raise in the apoptotic rates of both cell lines, ruled by a dose-dependent ROS accumulation detected after 4 h of incubation, which in turn was caused by HT direct inhibition of thioredoxin (Trx) reductase 1 (TrxR1), a key player in redox homeostasis .
|
[
{
"end": 46,
"label": "CellLine",
"start": 40,
"text": "HCT116"
},
{
"end": 108,
"label": "CellLine",
"start": 103,
"text": "SW620"
}
] |
ChemBL_V1
|
At higher concentrations, effects triggered by HT appear different and sometimes poorly reproducible.
|
[] |
ChemBL_V1
|
Treatment of Caco2 and HT-29 cell lines with 100 μM HT for 8 h led to G1 phase cell cycle arrest, whereas extending the treatment for 48 h caused activation of caspase-3.
|
[
{
"end": 18,
"label": "CellLine",
"start": 13,
"text": "Caco2"
},
{
"end": 28,
"label": "CellLine",
"start": 23,
"text": "HT-29"
}
] |
ChemBL_V1
|
Also, incubation of both cell lines with 150 μM for 8 h produced an increase in apoptosis rate, but HT contributed to the increase in the percentage of necrotic cells only in HT-29 cells .
|
[
{
"end": 180,
"label": "CellLine",
"start": 175,
"text": "HT-29"
}
] |
ChemBL_V1
|
After 24 and 48 h incubation, 6 ppm (≈39 μM) HT was not sufficient to decrease HT-29 cell viability, but after 72 h treatment, there was a significant cytotoxic effect, with IC50 = 12 ppm (≈78 μM).
|
[
{
"end": 84,
"label": "CellLine",
"start": 79,
"text": "HT-29"
}
] |
ChemBL_V1
|
At this concentration, HT elicited an increase in the transcription of tumor suppressor genes encoding for p21 and p27, while decreasing the expression of CCND1 (encoding for cyclin D1) .
|
[] |
ChemBL_V1
|
After 24 h, 100 μM HT showed no effect on cell viability of HT-29 cell line.
|
[
{
"end": 65,
"label": "CellLine",
"start": 60,
"text": "HT-29"
}
] |
ChemBL_V1
|
However, 72 h incubation with 100 μM HT efficaciously reduced cell viability of and triggered apoptosis in HT-29 cells .
|
[
{
"end": 112,
"label": "CellLine",
"start": 107,
"text": "HT-29"
}
] |
ChemBL_V1
|
On the contrary, another report demonstrated a dose-dependent increase in the apoptotic rates of HT-29, HCT-116, and LoVo cells as well as Dukes’ type B colorectal carcinoma cell line SW480 for 24 and 48 h treatment with 100–400 μM HT .
|
[
{
"end": 102,
"label": "CellLine",
"start": 97,
"text": "HT-29"
},
{
"end": 111,
"label": "CellLine",
"start": 104,
"text": "HCT-116"
},
{
"end": 121,
"label": "CellLine",
"start": 117,
"text": "LoVo"
},
{
"end": 189,
"label": "CellLine",
"start": 184,
"text": "SW480"
}
] |
ChemBL_V1
|
Further evidence supports HT-dependent reduction in cell viability of and induction of apoptosis in HT-29 cells also at higher concentrations (600–800 μM) , and one study documented IC50 = 750 μM for HT29 and HT29–19A cell lines .
|
[
{
"end": 105,
"label": "CellLine",
"start": 100,
"text": "HT-29"
},
{
"end": 204,
"label": "CellLine",
"start": 200,
"text": "HT29"
},
{
"end": 217,
"label": "CellLine",
"start": 209,
"text": "HT29–19A"
}
] |
ChemBL_V1
|
A more detailed analysis revealed that treatment of HT-29 cells with 400 μM HT for 24 h produced S and G2/M phase cell cycle arrest and induced apoptosis, flanked by apoptosis ruling events: loss of mitochondrial potential, decrease in anti-apoptotic Bcl-2 protein level, reduction in phosphorylation of Bad, increase in pro-apoptotic Bax and Bak, cytochrome c release, and activation of caspase-3 .
|
[
{
"end": 57,
"label": "CellLine",
"start": 52,
"text": "HT-29"
}
] |
ChemBL_V1
|
A similar S phase cell cycle arrest was also observed for 800 μM HT, and induction of apoptosis also took place after 24 h incubation of HT-29 cells with 600 μM and 800 μM HT .
|
[
{
"end": 142,
"label": "CellLine",
"start": 137,
"text": "HT-29"
}
] |
ChemBL_V1
|
A 16 h incubation with 400 μM HT triggered endoplasmic reticulum stress in HT-29 cells, with activation of unfolded protein response, as indicated by the increase in the spliced form of X-box binding protein 1 (XBP-1) mRNA, the upregulation of chaperone 78 kDa glucose-regulated protein (GRP78/Bip) at both mRNA and protein levels, the transient increase (after 2 h) in phosphorylation of PKR-like ER-associated kinase (PERK) and translation initiation factor-2 (eIF2a) (accounting for inhibition of protein synthesis), and time-dependent increase in CHOP protein levels (responsible for ROS production and Bcl-2 downregulation) and NADPH oxidase 4 (NOX4) .
|
[
{
"end": 80,
"label": "CellLine",
"start": 75,
"text": "HT-29"
}
] |
ChemBL_V1
|
In the same cellular model, apoptosis seemed regulated by HT-mediated increase in the phosphorylated form of c-jun N-terminal kinase (JNK), which is a central player in establishing cell faith (apoptosis vs. proliferation) .
|
[] |
ChemBL_V1
|
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