OTAR3088/AL_Test_data · Datasets at Hugging Face

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Also, 200 μg/mL OLE caused a reduction in Prdx-1 protein level after 8 h of treatment, which was maintained after 24 h .	[]	ChemBL_V1
Treatment of K562 cells with concentrations of HT up to 1000 μM produced a dose-dependent reduction in cell viability (EC50 = 147 μM) with concomitant increase in caspase 3/7 activity .	[ { "end": 17, "label": "CellLine", "start": 13, "text": "K562" } ]	ChemBL_V1
Acute monocytic leukemia is the expression formerly utilized to indicate a neoplastic lesion arising from the loss of normal maturation along the monocytic lineage, and is now included in the larger category labeled as acute myeloid leukemia (that is the most frequent leukemia among adults) .	[]	ChemBL_V1
THP-1 is probably the most known acute monocytic leukemia cell line.	[ { "end": 5, "label": "CellLine", "start": 0, "text": "THP-1" } ]	ChemBL_V1
Among all HT doses tested (1–40 μM), only 20 μM affected viability of THP-1 cells after 72 h .	[ { "end": 75, "label": "CellLine", "start": 70, "text": "THP-1" } ]	ChemBL_V1
Instead, in U937 cells (a human acute myeloid leukemia cell line of pro-monocytic origin) , 75 μM and 200 μM HT increased cell death and apoptosis .	[ { "end": 16, "label": "CellLine", "start": 12, "text": "U937" } ]	ChemBL_V1
T-cell acute lymphoblastic leukemia (T-ALL) represents the consequence of the loss of proper regulation of T-cell development, resulting in the accumulation of immature progenitors.	[]	ChemBL_V1
With conventional therapies, survival is lower among adult patients vs. pediatric subjects, mainly because of treatment-associated toxicity and higher relapse rates in adults .	[]	ChemBL_V1
Treatment of T-ALL cell line CCRF-CEM with HT concentrations up to 1000 μM produced a dose-dependent reduction in cell viability (EC50 = 338 μM), flanked by the increase in caspase 3/7 activity .	[ { "end": 37, "label": "CellLine", "start": 29, "text": "CCRF-CEM" } ]	ChemBL_V1
Despite being considered as a T-ALL cell line, Jurkat cells are immunophenotypically different from T-ALL cells; thus, results obtained in this cell model retain modest reliability .	[ { "end": 53, "label": "CellLine", "start": 47, "text": "Jurkat" } ]	ChemBL_V1
A study performed using an HT-rich natural extract of the olive pulp as a source of HT demonstrated a dose-dependent reduction in cell viability and induction of apoptosis, together with ROS accumulation .	[]	ChemBL_V1
As the literature analysis in Section 2 and Section 3 corroborates, methodological standardization for the study of the effects of natural products may reveal to be challenging, mainly as a consequence of the combination of the multiplicity of molecular patterns triggered and effects elicited by these substances, together with the intrinsic variability of the biological systems (cancer cells and interaction with the surrounding tissue cells) of interest.	[]	ChemBL_V1
The dissertation above seems to validate the use of OLE and HT as cytotoxic agents, with the chance of a further employment of both compounds as microenvironment modulators (OLE- and HT-dependent effects on cancer cell viability and behavior are summarized in Figure 2).	[]	ChemBL_V1
However, before extrapolating any conclusion, the reported data should be interpreted and discussed in the light of factors determining the feasibility of such a purpose.	[]	ChemBL_V1
In the next paragraphs, we discuss the role of OLE and HT absorption, bioavailability and toxicity to non-cancer cells, OLE and HT interaction with chemotherapy drugs, OLE- and HT-mediated repercussions on drug metabolism, and OLE and HT antioxidant activity in the context of chemotherapy-induced oxidative stress as determinants of the net OLE and HT activity on cancer insurgence and growth in humans.	[]	ChemBL_V1
Factors influencing OLE and HT effects in human cancers are reported in Figure 2.	[]	ChemBL_V1
Information about OLE and HT absorption through the digestive tract and bioavailability is limited, and often arises from a combination of experimental proofs obtained from humans and animal models.	[]	ChemBL_V1
After ingestion, OLE remains mostly stable in the acid gastric environment, although non-enzymatic hydrolysis may account for an increased amount of HT reaching the small intestine.	[]	ChemBL_V1
OLE is poorly absorbed through the small intestine (mainly via diffusion), as demonstrated in rats and humans, enters systemic circulation, undergoes sulphate and glucuronide conjugation and/or enzymatic conversion in HT, and is eliminated in urine mainly as aglycon and glucuronide derivatives .	[]	ChemBL_V1
In the large intestine, OLE is metabolized by gut microbiota, producing HT .	[]	ChemBL_V1
After ingestion, HT is more largely absorbed in the intestine by diffusion, is mainly metabolized into glucuronide and sulphate conjugates, and is excreted in urine mostly in its glucuronide conjugated form .	[]	ChemBL_V1
For both OLE and HT (and their metabolites), the maximum excretion rate is reached in 4 h in humans .	[]	ChemBL_V1
All these aspects may represent a potential source of difficulties if the objective is achieving and maintaining pharmacologically relevant concentrations of OLE and HT in plasma after ingestion.	[]	ChemBL_V1
Whenever performing a critical evaluation of OLE and HT availability, data from animal models should be taken into account with caution, since it has been demonstrated that the rate of excretion of HT differs between humans and rats (being more rapid in humans) .	[]	ChemBL_V1
Thus, only data related to OLE and HT plasma concentrations in humans are listed in this section.	[]	ChemBL_V1
In a group of volunteers, the efficacy of OLE delivery was assayed for liquid and capsule preparations, each containing a lower (64 mg total olive phenols, with 51.1 mg OLE) or a higher (96 mg total, with 76.6 mg OLE) dose.	[]	ChemBL_V1
The best performance was offered by higher dose liquid preparation, with a mean peak of plasma OLE ± S.D. = 3.55 ± 2.27 ng/mL and a mean time to peak ± S.D. = 20 ± 12 min, whereas the worst OLE peak plasma values were detected for the lower dose capsule preparation (mean peak ± S.D. = 0.52 ± 0.24 ng/mL, mean time to peak ± S.D. = 40 ± 27 min) .	[]	ChemBL_V1
In humans, the assumption of 5 mg HT added to extra virgin olive oil produced a plasma peak of 3.79 ng/mL after 30 min, followed by a rapid decline in HT plasma concentration (minimum reached value < 2 ng/mL after 240 min) .	[]	ChemBL_V1
This result matched another report documenting that the consumption of HT-enriched biscuits (containing 5.25 mg HT) determined the appearance of HT metabolites in the volunteers’ plasma between 30 min and 1 h .	[]	ChemBL_V1
A similar pharmacokinetic effect was reported in other experimental settings using olive-derived watery supplements as a source of HT .	[]	ChemBL_V1
The ingestion of 40 mL of high (366 mg/kg)-phenolic-compound-content olive oil led to a plasma HT concentration peak of ≈15 μM (mean time to peak ± S.D. = 0.91 ± 0.84 h, mean estimated elimination half-life ± S.D. = 3.00 ± 1.46 h), whereas the same amount of low- (2.7 mg/kg) and medium (164 mg/kg)-phenolic-compound-content olive oil produced an HT peak of ≈5 μM or less .	[]	ChemBL_V1
The assumption of 25 mL of extra virgin olive oil led to a maximum plasma concentration = 4.4 ng/mL, (time to peak = 0.25 h) , and the ingestion of 25 mL of low-phenolic-content (10 mg/kg), moderate-phenolic-content (133 mg/kg), and high-phenolic-content (486 mg/kg) olive oil produce a plasma HT peak of ≈5 nM, 25 nM, and 50 nM, respectively .	[]	ChemBL_V1
On the basis of these pieces of data, it becomes evident that cytotoxicity and anti-cancer effects of OLE and HT were recorded at concentrations largely exceeding those reachable with diet/olive oil consumption, and OLE and HT pharmacokinetics does not match the requested treatment duration to exert an anti-proliferative effect.	[]	ChemBL_V1
Thus, it is difficult to imagine how OLE and HT may be used as cancer-preventive/treating agents if the route of administration is ingestion.	[]	ChemBL_V1
Also, given that both phenols are extensively metabolized and rapidly excreted, the safety and efficacy of other routes of administration (e.g., intravenous) should be assessed in detail.	[]	ChemBL_V1
However, even at high concentrations, OLE and HT seem to be selectively cytotoxic for cancer cells, with no or negligible/minimal effects on non-cancer cells, as demonstrated for embryonic rat cardiomyoblasts H9c2(2-1), human breast epithelial cell line MCF-10A , nonmalignant human bronchial epithelial BEAS-2B cell line , normal colonic cell line CCD-841CoN , human normal liver cell line (HL-7702) , human normal prostate epithelial cells PWLE2 , human bile duct cell line HIBEpiC , human fibroblasts WI-38 , normal skin fibroblast cell line WS1 , human GN61 gingival fibroblasts , human lymphocytes , human PBMCs , and normal human fibroblasts .	[ { "end": 213, "label": "CellLine", "start": 209, "text": "H9c2" }, { "end": 261, "label": "CellLine", "start": 254, "text": "MCF-10A" }, { "end": 311, "label": "CellLine", "start": 304, "text": "BEAS-2B" }, { "end": 359, "label": "CellLine", "start": 349, "text": "CCD-841CoN" }, { "end": 399, "label": "CellLine", "start": 392, "text": "HL-7702" }, { "end": 447, "label": "CellLine", "start": 442, "text": "PWLE2" }, { "end": 483, "label": "CellLine", "start": 476, "text": "HIBEpiC" }, { "end": 509, "label": "CellLine", "start": 504, "text": "WI-38" }, { "end": 548, "label": "CellLine", "start": 545, "text": "WS1" } ]	ChemBL_V1
Thus, OLE and HT are generally considered safe on the basis of experimental data, despite sporadic reports against the trend, as happened for HT, which proved to be toxic for human non-tumorigenic pancreas cells HPDE and human normal prostate RWPE-1 cells .	[ { "end": 216, "label": "CellLine", "start": 212, "text": "HPDE" }, { "end": 249, "label": "CellLine", "start": 243, "text": "RWPE-1" } ]	ChemBL_V1
The evaluation of OLE and HT safety profile in cancer patients is still pending.	[]	ChemBL_V1
Some experimental proof has demonstrated that OLE and HT may potentiate the effect of both routinely employed and new potential anti-cancer drugs .	[]	ChemBL_V1
In human melanoma cell line A375, the combination of 250 μM OLE with alkylating agent dacarbazine was more effective in reducing cell viability than dacarbazine alone .	[ { "end": 32, "label": "CellLine", "start": 28, "text": "A375" } ]	ChemBL_V1
In female breast cancer patients undergoing neoadjuvant chemotherapy, orally administered 15 mg/kg HT determined a significant decrease in plasma levels of TIMP-1 during treatment with epirubicin and cyclophosphamide .	[]	ChemBL_V1
In an in vivo model of tumor xenograft (triple negative MDA-MB-231 cell line) in BALB/c OlaHsd-foxn1 mice, peritoneally injected 50 mg/kg OLE for 4 weeks exhibited a synergistic effect with doxorubicin on inhibition of tumor growth and induction of apoptosis .	[ { "end": 66, "label": "CellLine", "start": 56, "text": "MDA-MB-231" }, { "end": 87, "label": "CellLine", "start": 81, "text": "BALB/c" } ]	ChemBL_V1
Combination of paclitaxel with HT reduced MCF-7 and MDA-MB-231 cell viability in vitro, and tumor volume in breast cancer-bearing Sprague–Dawley rats (in vivo injected HT dose = 0.5 mg/kg/day) .	[ { "end": 47, "label": "CellLine", "start": 42, "text": "MCF-7" }, { "end": 62, "label": "CellLine", "start": 52, "text": "MDA-MB-231" } ]	ChemBL_V1
In HT-29 and WiDr colorectal cancer cell lines, combination of 10 μM HT and monoclonal anti-epidermal growth factor receptor (EGFR) antibody cetuximab reduced cell growth, both in the presence and in the absence of epidermal growth factor (EGF) stimulation, inducing G1/S and G2/M phase cell cycle arrest .	[ { "end": 8, "label": "CellLine", "start": 3, "text": "HT-29" }, { "end": 17, "label": "CellLine", "start": 13, "text": "WiDr" } ]	ChemBL_V1
In human osteosarcoma MG-63 cell line, 20 μg/mL (≈37 μM) OLE had an additive effect on anthracycline Adriamycin-induced reduction in cell viability, with a mechanism that did not alter the G2/M phase blockade elicited by Adriamycin .	[ { "end": 27, "label": "CellLine", "start": 22, "text": "MG-63" } ]	ChemBL_V1
Similarly, in 143B osteosarcoma cells, OLE showed a synergistic, antiproliferative, and anti-migratory effect in combination with estradiol metabolite 2-methoxyestradiol at all OLE concentrations tested (1–250 μM for proliferation, and 100 μM for wound healing assay) .	[ { "end": 18, "label": "CellLine", "start": 14, "text": "143B" } ]	ChemBL_V1
On the contrary, HT did not modify doxorubicin-mediated growth inhibition of human osteosarcoma cells U-2 OS .	[ { "end": 108, "label": "CellLine", "start": 102, "text": "U-2 OS" } ]	ChemBL_V1
In neuroblastoma cells T98G, 277.5 μM and 555 μM OLE showed a synergistic effect with alkylating agent temozolomide on cell viability, increasing the expression of miRNAs involved in tumor growth suppression, mainly Let-7d .	[ { "end": 27, "label": "CellLine", "start": 23, "text": "T98G" } ]	ChemBL_V1
OLE and HT may also magnify the efficacy of other types of cancer treatment.	[]	ChemBL_V1
In nasopharyngeal cancer cell line HNE1 and HONE1, 200 μM OLE enhanced cell radiosensitivity in vitro and in vivo after injection in BALB/C nude mice, with a mechanism involving OLE-dependent removal of HIF-1α hypoxic repression exerted at miR-519d promoter region, upregulation of miR-519d, and miR-519d targeting of DNA damage-regulated protein 1 (PDRG1) .	[ { "end": 39, "label": "CellLine", "start": 35, "text": "HNE1" }, { "end": 49, "label": "CellLine", "start": 44, "text": "HONE1" }, { "end": 139, "label": "CellLine", "start": 133, "text": "BALB/C" } ]	ChemBL_V1
Despite these encouraging results, since both OLE and HT may act as transcriptional regulators and are extensively metabolized by the liver (see sections above), a careful analysis of the effects of both phenols on phase I and phase II enzyme kinetics and expression should be performed before considering the use of OLE and HT during chemotherapeutic treatments.	[]	ChemBL_V1
Preliminary data obtained in human liver microsomes point towards OLE-mediated inhibition of CY3A and CYP1A2 activity .	[]	ChemBL_V1
On the contrary, a study performed in 129/Sv WT and Ppara-null mice demonstrated that OLE (ingested with food, thus absorbed through the intestinal wall) stimulated the transcription of cytochrome P450 genes Cyp1a1, Cyp1a2, Cyp1b1, Cyp3a14, Cyp3a25, Cyp2c29, Cyp2c44, Cyp2d22, and Cyp2e1 in the liver, with a mechanism mediated by peroxisome proliferator-activated receptor α (PPARα) .	[]	ChemBL_V1
Studies defining the effects of OLE and HT on the expression of and interaction with phase I and phase II enzymes are still missing, but they should be considered absolutely necessary in order to determine if OLE and HT are able to modify the metabolism of other drugs.	[]	ChemBL_V1
Besides their possible synergic/additive actions, OLE and HT might also be seen as useful support agents during cancer treatment.	[]	ChemBL_V1
A lot of experimental data in vivo and in vitro have definitively demonstrated the ROS scavenger ability of OLE and HT, which can also act on antioxidant cellular mechanisms restoring ROS homeostasis, including promotion of the increase in reduced glutathione levels (GSH), depletion of lipid peroxidation product malondialdehyde (MDA), intensification of the expression and/or activity of detoxicating enzymes SOD, CAT, glutathione-S-transferase (GST), and glutathione peroxidase (GSH-Px), and nuclear factor E2-related factor 2 (Nrf2) upregulation/transactivation, which in turn regulates the expression of fundamental enzymes protecting cells from oxidative damage, like HO-1 .	[]	ChemBL_V1
Radical and non-radical ROS (including hydrogen peroxide H2O2, superoxide anion radical O2, and hydroxyl radical OH) may have a pro-tumorigenic effect; they are involved in cancer insurgence determining DNA damage, genomic instability, and interference with signalling and metabolic pathways, enhance cell proliferation through the activation of pro-survival pathways in cancer cells while promoting the reorganization of cellular antioxidant capacities and adaptation to hypoxic conditions, are involved in the development of anti-cancer therapy resistance (through the expansion of cell antioxidant capacities), push the activation of metastasis cellular programs via EMT, and boost immunosuppression and angiogenesis in the cancer microenvironment.	[]	ChemBL_V1
However, if ROS concentration overcomes cancer cell defenses against oxidative stress and damage, or cancer cell-produced ROS balance is perturbated, ROS may account for fatal cell damage and trigger apoptosis .	[]	ChemBL_V1
This may explain the fact that the mechanism of action of some common cancer treatments (e.g., radiation, inorganic compounds, tyrosine kinase inhibitors, monoclonal antibodies, protease inhibitors, pyrimidine analogues, alkylating agents, and anthracyclines) relies on oxidative stress and ROS-dependent apoptosis .	[]	ChemBL_V1
OLE and HT cytotoxic actions themselves in part depend on ROS generation ; moreover, 200 μM OLE reduced HIF-1α mRNA and protein levels in HNE-1 and HONE-1 nasopharyngeal cancer cell lines , and pro-apoptotic OLE concentration corresponding to 100 μM was able to increase ROS production in MDA-MB-231 cell line, with the maximum peak obtained after 4 h incubation .	[ { "end": 143, "label": "CellLine", "start": 138, "text": "HNE-1" }, { "end": 154, "label": "CellLine", "start": 148, "text": "HONE-1" }, { "end": 299, "label": "CellLine", "start": 289, "text": "MDA-MB-231" } ]	ChemBL_V1
ROS-mediated damage at least in part accounts for chemotherapy-dependent toxicity detected at the tissue level on non-cancer cells .	[]	ChemBL_V1
However, OLE and HT have shown an important ability to mitigate the toxicity elicited by chemotherapeutic agents mainly through their largely demonstrated antioxidant and ROS scavenger activity.	[]	ChemBL_V1
In fact, in vivo, 50 mg/kg, 100 mg/kg, and 200 mg/kg OLE showed a dose-dependent antioxidant activity, accounting for amelioration of cisplatin-induced pancreatic, liver, lung, and stomach damage in Spraque–Dawley rats .	[]	ChemBL_V1
In the same in vivo model of cisplatin-induced oxidative stress, 50 mg/kg, 100 mg/kg, and 200 mg/kg OLE improved anemia, thrombocytopenia, and leukopenia .	[]	ChemBL_V1
In cyclophosphamide- and epirubicin-induced toxicity in Sprague–Dawley rats, four cycles of 150 mg/kg/week OLE reduced lipid peroxidation and increased the activity of antioxidant enzymes in heart, kidney, and liver .	[]	ChemBL_V1
Moreover, in a model of cyclophosphamide-induced immunosuppression in broilers, a solution containing 200 mg/L HT reduced duodenal MDA levels while increasing the activity of antioxidant enzymes .	[]	ChemBL_V1
In vitro, 50 μM and 70 μM HT reduced doxorubicin-mediated toxicity in embryonic rat cardiomyoblasts H9c2(2-1) after 48 h incubation.	[ { "end": 104, "label": "CellLine", "start": 100, "text": "H9c2" } ]	ChemBL_V1
Also, 24 and 48 h incubation with 50 μM HT reduced doxorubicin-dependent intracellular ROS accumulation, increasing SOD2 levels and protecting cells from doxorubicin-induced apoptosis .	[]	ChemBL_V1
OLE- and HT-dependent redox homeostasis restoration might represent a potential issue with respect to OLE and HT use at nutritionally relevant concentrations as both anticancer drugs and detoxicating agents (especially during chemotherapy).	[]	ChemBL_V1
Low concentrations of both OLE and HT (10 μM) protected HL-60 and PBMCs from H2O2-induced DNA damage, and lymphocytes from PMA-stimulated monocyte-mediated oxidative DNA damage .	[ { "end": 61, "label": "CellLine", "start": 56, "text": "HL-60" } ]	ChemBL_V1
This piece of information sounds particularly alarming, since arsenic trioxide (As2O3) is one of the agents utilized to treat acute promyelocytic leukemia, especially in combinatory first-line therapy, and its mechanism of action relies on ROS increase .	[]	ChemBL_V1
Incubation with 30 μM HT for 48 h was not sufficient to reduce viability of Hep3B cells, but significantly improved cellular antioxidant capacities .	[ { "end": 81, "label": "CellLine", "start": 76, "text": "Hep3B" } ]	ChemBL_V1
Similarly, 5–200 μM HT was ineffective as a cytotoxic reagent, but reduced the level of oxidative stress in MCF-7 cells after 16 h incubation .	[ { "end": 113, "label": "CellLine", "start": 108, "text": "MCF-7" } ]	ChemBL_V1
Erastin is a ferropoptosis inducer that is currently under evaluation as an anti-cancer treatment .	[]	ChemBL_V1
In ovarian carcinoma HEY cells, 100 μM OLE was not able to affect cell viability, but acted as an antioxidant, decreasing endogenous and erastin-dependent LIP and ROS levels, preventing erastin-dependent ROS accumulation in mytochondria and increasing glutathione peroxidase 4 (GPX4) levels that were reduced by erastin treatment, finally counteracting erastin-induced cell death .	[ { "end": 24, "label": "CellLine", "start": 21, "text": "HEY" } ]	ChemBL_V1
It remains to be demonstrated if nutritionally relevant and/or non-cytotoxic concentrations of OLE and HT may offer a survival advantage to neoplastic cells.	[]	ChemBL_V1
A similar scenario has been described for other antioxidants (e.g., N-acetyl-L-cysteine, alpha-tocopherol and carotenoids), which showed a pro-tumorigenic action by exerting beneficial effects on cancer cells .	[]	ChemBL_V1
It will be fundamental to deepen these pieces of data in order to rule out the chance that OLE and HT may promote cancer growth and metastasis.	[]	ChemBL_V1
Another risk factor for tumorigenesis is inflammation.	[]	ChemBL_V1
ROS imbalance itself may drive inflammation, inducing the production of pro-inflammatory cytokines interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor-α (TNF-α) .	[]	ChemBL_V1
Persisting (chronic) or poorly controlled inflammation may directly promote tumorigenesis due to the action of ROS and the recruitment of immune cells triggering the release of growth signals and the activation of tissue repair mechanisms.	[]	ChemBL_V1
After cancer insurgence, the production of inflammatory mediators sustained by cancer cells and surrounding actors (tissue macrophages, cancer-associated fibroblast, infiltrating immune cells, and endothelial cells, among the others) contributes to the creation of an environment favoring immune evasion, cell survival, invasion, and angiogenesis.	[]	ChemBL_V1
Chemotherapy may also account for an exacerbation of inflammation, whose biological meaning is poorly understood, being recognized as immune-activating as well as a contributor to the failure of the therapeutic regimen .	[]	ChemBL_V1
OLE and HT exhibit an anti-inflammatory activity that has been demonstrated in multiple in vivo and in vitro models, although some experimental variables related to the timing of administration of inflammatory stimuli might have affected the reproducibility of the results, mainly in vitro, and nutritionally relevant concentrations of OLE and HT often showed no anti-inflammatory activity on human peripheral blood mononuclear cells .	[]	ChemBL_V1
Proof of OLE and HT modulation of inflammation in cancer cells has been obtained mostly from colorectal cancer.	[]	ChemBL_V1
In an in vivo model of AOM/DSS-induced colorectal cancer in C57BL/6 mice, 50 mg/kg and 100 mg/kg OLE reduced IL-6, TNF-α, and IFN-γ colon tissue levels, as well as COX-2 levels .	[ { "end": 67, "label": "CellLine", "start": 60, "text": "C57BL/6" } ]	ChemBL_V1
Treatment of HCT116 and LoVo cells with 0.0154 mg/mL (≈100 μM) HT and 0.0231 mg/mL (≈150 μM) HT, respectively, for 72 h reduced phosphorylation of NF-κB p65, in turn leading to a reduction in pro-inflammatory cytokines TNF-α and IL-8 at both mRNA and protein levels.	[ { "end": 19, "label": "CellLine", "start": 13, "text": "HCT116" }, { "end": 28, "label": "CellLine", "start": 24, "text": "LoVo" } ]	ChemBL_V1
HT-dependent anti-inflammatory effect was also mediated by HT-elicited increase in protein levels of PPARγ.	[]	ChemBL_V1
In addition, HT acted as a PPARγ agonist, promoting its transcriptional activity .	[]	ChemBL_V1
In HT-29 cell line, 100–400 μM reduced TNF-α-induced NF-κB activation in a dose-dependent manner .	[ { "end": 8, "label": "CellLine", "start": 3, "text": "HT-29" } ]	ChemBL_V1
In in vitro models, the frame appears completely different.	[]	ChemBL_V1
The only HT concentrations that elicited a reduction in IL-6 levels were 80 μM for HepG2 and 30 μM for Hep3B.	[ { "end": 88, "label": "CellLine", "start": 83, "text": "HepG2" }, { "end": 108, "label": "CellLine", "start": 103, "text": "Hep3B" } ]	ChemBL_V1
HT doses of 100 μM and 200 μM in HepG2 and 80 μM, 100 μM, and 200 μM in Hep3B cells produced an increase in IL-6 release .	[ { "end": 38, "label": "CellLine", "start": 33, "text": "HepG2" }, { "end": 77, "label": "CellLine", "start": 72, "text": "Hep3B" } ]	ChemBL_V1
Treatment of K562 cells with 100 μM HT produced transcriptional effects including the downregulation of IL-10 receptor and the upregulation of inflammatory mediators IL-6 and IL-8 .	[ { "end": 17, "label": "CellLine", "start": 13, "text": "K562" } ]	ChemBL_V1
OLE and HT may participate in control of cancer-associated and chemotherapy-dependent tissue inflammation by acting on non-tumor cells.	[]	ChemBL_V1
As demonstrated in vivo, treatment of BALB/cN mice with 5, 10, and 20 mg/kg OLE suppressed signs of cisplatin-induced renal inflammation, including tissue modulation of TNF-α levels .	[]	ChemBL_V1
Four cycles of 150 mg/kg/week OLE in Sprague–Dawley rats reduced serum TNF-α and IL-6 in an experimental model of epirubicin and cyclophosphamide toxicity .	[]	ChemBL_V1
In a model of cyclophosphamide-induced immunosuppression in broilers, a solution containing 200 mg/L HT promoted the duodenal expression of anti-inflammatory cytokines IL-4 and IL-10 .	[]	ChemBL_V1
It remains to be assessed if such a modulatory activity is able to contribute to the immunosuppressant environment surrounding cancer cells.	[]	ChemBL_V1
From the analysis of the literature reported in this review, it becomes evident that the multifaceted nature of OLE and HT interaction with molecular mediators in cancer cells and non-cancer tissues determines the need for safe strategies to improve OLE and HT bioavailability and delivery, also offering a more stable and highly selective anti-proliferative activity throughout time.	[]	ChemBL_V1

Also, 200 μg/mL OLE caused a reduction in Prdx-1 protein level after 8 h of treatment, which was maintained after 24 h .

[]

ChemBL_V1

Treatment of K562 cells with concentrations of HT up to 1000 μM produced a dose-dependent reduction in cell viability (EC50 = 147 μM) with concomitant increase in caspase 3/7 activity .

[ { "end": 17, "label": "CellLine", "start": 13, "text": "K562" } ]

ChemBL_V1

Acute monocytic leukemia is the expression formerly utilized to indicate a neoplastic lesion arising from the loss of normal maturation along the monocytic lineage, and is now included in the larger category labeled as acute myeloid leukemia (that is the most frequent leukemia among adults) .

[]

ChemBL_V1

THP-1 is probably the most known acute monocytic leukemia cell line.

[ { "end": 5, "label": "CellLine", "start": 0, "text": "THP-1" } ]

ChemBL_V1

Among all HT doses tested (1–40 μM), only 20 μM affected viability of THP-1 cells after 72 h .

[ { "end": 75, "label": "CellLine", "start": 70, "text": "THP-1" } ]

ChemBL_V1

Instead, in U937 cells (a human acute myeloid leukemia cell line of pro-monocytic origin) , 75 μM and 200 μM HT increased cell death and apoptosis .

[ { "end": 16, "label": "CellLine", "start": 12, "text": "U937" } ]

ChemBL_V1

T-cell acute lymphoblastic leukemia (T-ALL) represents the consequence of the loss of proper regulation of T-cell development, resulting in the accumulation of immature progenitors.

[]

ChemBL_V1

With conventional therapies, survival is lower among adult patients vs. pediatric subjects, mainly because of treatment-associated toxicity and higher relapse rates in adults .

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ChemBL_V1

Treatment of T-ALL cell line CCRF-CEM with HT concentrations up to 1000 μM produced a dose-dependent reduction in cell viability (EC50 = 338 μM), flanked by the increase in caspase 3/7 activity .

[ { "end": 37, "label": "CellLine", "start": 29, "text": "CCRF-CEM" } ]

ChemBL_V1

Despite being considered as a T-ALL cell line, Jurkat cells are immunophenotypically different from T-ALL cells; thus, results obtained in this cell model retain modest reliability .

[ { "end": 53, "label": "CellLine", "start": 47, "text": "Jurkat" } ]

ChemBL_V1

A study performed using an HT-rich natural extract of the olive pulp as a source of HT demonstrated a dose-dependent reduction in cell viability and induction of apoptosis, together with ROS accumulation .

[]

ChemBL_V1

As the literature analysis in Section 2 and Section 3 corroborates, methodological standardization for the study of the effects of natural products may reveal to be challenging, mainly as a consequence of the combination of the multiplicity of molecular patterns triggered and effects elicited by these substances, together with the intrinsic variability of the biological systems (cancer cells and interaction with the surrounding tissue cells) of interest.

[]

ChemBL_V1

The dissertation above seems to validate the use of OLE and HT as cytotoxic agents, with the chance of a further employment of both compounds as microenvironment modulators (OLE- and HT-dependent effects on cancer cell viability and behavior are summarized in Figure 2).

[]

ChemBL_V1

However, before extrapolating any conclusion, the reported data should be interpreted and discussed in the light of factors determining the feasibility of such a purpose.

[]

ChemBL_V1

In the next paragraphs, we discuss the role of OLE and HT absorption, bioavailability and toxicity to non-cancer cells, OLE and HT interaction with chemotherapy drugs, OLE- and HT-mediated repercussions on drug metabolism, and OLE and HT antioxidant activity in the context of chemotherapy-induced oxidative stress as determinants of the net OLE and HT activity on cancer insurgence and growth in humans.

[]

ChemBL_V1

Factors influencing OLE and HT effects in human cancers are reported in Figure 2.

[]

ChemBL_V1

Information about OLE and HT absorption through the digestive tract and bioavailability is limited, and often arises from a combination of experimental proofs obtained from humans and animal models.

[]

ChemBL_V1

After ingestion, OLE remains mostly stable in the acid gastric environment, although non-enzymatic hydrolysis may account for an increased amount of HT reaching the small intestine.

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OLE is poorly absorbed through the small intestine (mainly via diffusion), as demonstrated in rats and humans, enters systemic circulation, undergoes sulphate and glucuronide conjugation and/or enzymatic conversion in HT, and is eliminated in urine mainly as aglycon and glucuronide derivatives .

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In the large intestine, OLE is metabolized by gut microbiota, producing HT .

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After ingestion, HT is more largely absorbed in the intestine by diffusion, is mainly metabolized into glucuronide and sulphate conjugates, and is excreted in urine mostly in its glucuronide conjugated form .

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For both OLE and HT (and their metabolites), the maximum excretion rate is reached in 4 h in humans .

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All these aspects may represent a potential source of difficulties if the objective is achieving and maintaining pharmacologically relevant concentrations of OLE and HT in plasma after ingestion.

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Whenever performing a critical evaluation of OLE and HT availability, data from animal models should be taken into account with caution, since it has been demonstrated that the rate of excretion of HT differs between humans and rats (being more rapid in humans) .

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Thus, only data related to OLE and HT plasma concentrations in humans are listed in this section.

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In a group of volunteers, the efficacy of OLE delivery was assayed for liquid and capsule preparations, each containing a lower (64 mg total olive phenols, with 51.1 mg OLE) or a higher (96 mg total, with 76.6 mg OLE) dose.

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The best performance was offered by higher dose liquid preparation, with a mean peak of plasma OLE ± S.D. = 3.55 ± 2.27 ng/mL and a mean time to peak ± S.D. = 20 ± 12 min, whereas the worst OLE peak plasma values were detected for the lower dose capsule preparation (mean peak ± S.D. = 0.52 ± 0.24 ng/mL, mean time to peak ± S.D. = 40 ± 27 min) .

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In humans, the assumption of 5 mg HT added to extra virgin olive oil produced a plasma peak of 3.79 ng/mL after 30 min, followed by a rapid decline in HT plasma concentration (minimum reached value < 2 ng/mL after 240 min) .

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This result matched another report documenting that the consumption of HT-enriched biscuits (containing 5.25 mg HT) determined the appearance of HT metabolites in the volunteers’ plasma between 30 min and 1 h .

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A similar pharmacokinetic effect was reported in other experimental settings using olive-derived watery supplements as a source of HT .

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The ingestion of 40 mL of high (366 mg/kg)-phenolic-compound-content olive oil led to a plasma HT concentration peak of ≈15 μM (mean time to peak ± S.D. = 0.91 ± 0.84 h, mean estimated elimination half-life ± S.D. = 3.00 ± 1.46 h), whereas the same amount of low- (2.7 mg/kg) and medium (164 mg/kg)-phenolic-compound-content olive oil produced an HT peak of ≈5 μM or less .

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The assumption of 25 mL of extra virgin olive oil led to a maximum plasma concentration = 4.4 ng/mL, (time to peak = 0.25 h) , and the ingestion of 25 mL of low-phenolic-content (10 mg/kg), moderate-phenolic-content (133 mg/kg), and high-phenolic-content (486 mg/kg) olive oil produce a plasma HT peak of ≈5 nM, 25 nM, and 50 nM, respectively .

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On the basis of these pieces of data, it becomes evident that cytotoxicity and anti-cancer effects of OLE and HT were recorded at concentrations largely exceeding those reachable with diet/olive oil consumption, and OLE and HT pharmacokinetics does not match the requested treatment duration to exert an anti-proliferative effect.

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Thus, it is difficult to imagine how OLE and HT may be used as cancer-preventive/treating agents if the route of administration is ingestion.

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Also, given that both phenols are extensively metabolized and rapidly excreted, the safety and efficacy of other routes of administration (e.g., intravenous) should be assessed in detail.

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However, even at high concentrations, OLE and HT seem to be selectively cytotoxic for cancer cells, with no or negligible/minimal effects on non-cancer cells, as demonstrated for embryonic rat cardiomyoblasts H9c2(2-1), human breast epithelial cell line MCF-10A , nonmalignant human bronchial epithelial BEAS-2B cell line , normal colonic cell line CCD-841CoN , human normal liver cell line (HL-7702) , human normal prostate epithelial cells PWLE2 , human bile duct cell line HIBEpiC , human fibroblasts WI-38 , normal skin fibroblast cell line WS1 , human GN61 gingival fibroblasts , human lymphocytes , human PBMCs , and normal human fibroblasts .

[ { "end": 213, "label": "CellLine", "start": 209, "text": "H9c2" }, { "end": 261, "label": "CellLine", "start": 254, "text": "MCF-10A" }, { "end": 311, "label": "CellLine", "start": 304, "text": "BEAS-2B" }, { "end": 359, "label": "CellLine", "start": 349, "text": "CCD-841CoN" }, { "end": 399, "label": "CellLine", "start": 392, "text": "HL-7702" }, { "end": 447, "label": "CellLine", "start": 442, "text": "PWLE2" }, { "end": 483, "label": "CellLine", "start": 476, "text": "HIBEpiC" }, { "end": 509, "label": "CellLine", "start": 504, "text": "WI-38" }, { "end": 548, "label": "CellLine", "start": 545, "text": "WS1" } ]

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Thus, OLE and HT are generally considered safe on the basis of experimental data, despite sporadic reports against the trend, as happened for HT, which proved to be toxic for human non-tumorigenic pancreas cells HPDE and human normal prostate RWPE-1 cells .

[ { "end": 216, "label": "CellLine", "start": 212, "text": "HPDE" }, { "end": 249, "label": "CellLine", "start": 243, "text": "RWPE-1" } ]

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The evaluation of OLE and HT safety profile in cancer patients is still pending.

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Some experimental proof has demonstrated that OLE and HT may potentiate the effect of both routinely employed and new potential anti-cancer drugs .

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In human melanoma cell line A375, the combination of 250 μM OLE with alkylating agent dacarbazine was more effective in reducing cell viability than dacarbazine alone .

[ { "end": 32, "label": "CellLine", "start": 28, "text": "A375" } ]

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In female breast cancer patients undergoing neoadjuvant chemotherapy, orally administered 15 mg/kg HT determined a significant decrease in plasma levels of TIMP-1 during treatment with epirubicin and cyclophosphamide .

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In an in vivo model of tumor xenograft (triple negative MDA-MB-231 cell line) in BALB/c OlaHsd-foxn1 mice, peritoneally injected 50 mg/kg OLE for 4 weeks exhibited a synergistic effect with doxorubicin on inhibition of tumor growth and induction of apoptosis .

[ { "end": 66, "label": "CellLine", "start": 56, "text": "MDA-MB-231" }, { "end": 87, "label": "CellLine", "start": 81, "text": "BALB/c" } ]

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Combination of paclitaxel with HT reduced MCF-7 and MDA-MB-231 cell viability in vitro, and tumor volume in breast cancer-bearing Sprague–Dawley rats (in vivo injected HT dose = 0.5 mg/kg/day) .

[ { "end": 47, "label": "CellLine", "start": 42, "text": "MCF-7" }, { "end": 62, "label": "CellLine", "start": 52, "text": "MDA-MB-231" } ]

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In HT-29 and WiDr colorectal cancer cell lines, combination of 10 μM HT and monoclonal anti-epidermal growth factor receptor (EGFR) antibody cetuximab reduced cell growth, both in the presence and in the absence of epidermal growth factor (EGF) stimulation, inducing G1/S and G2/M phase cell cycle arrest .

[ { "end": 8, "label": "CellLine", "start": 3, "text": "HT-29" }, { "end": 17, "label": "CellLine", "start": 13, "text": "WiDr" } ]

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In human osteosarcoma MG-63 cell line, 20 μg/mL (≈37 μM) OLE had an additive effect on anthracycline Adriamycin-induced reduction in cell viability, with a mechanism that did not alter the G2/M phase blockade elicited by Adriamycin .

[ { "end": 27, "label": "CellLine", "start": 22, "text": "MG-63" } ]

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Similarly, in 143B osteosarcoma cells, OLE showed a synergistic, antiproliferative, and anti-migratory effect in combination with estradiol metabolite 2-methoxyestradiol at all OLE concentrations tested (1–250 μM for proliferation, and 100 μM for wound healing assay) .

[ { "end": 18, "label": "CellLine", "start": 14, "text": "143B" } ]

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On the contrary, HT did not modify doxorubicin-mediated growth inhibition of human osteosarcoma cells U-2 OS .

[ { "end": 108, "label": "CellLine", "start": 102, "text": "U-2 OS" } ]

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In neuroblastoma cells T98G, 277.5 μM and 555 μM OLE showed a synergistic effect with alkylating agent temozolomide on cell viability, increasing the expression of miRNAs involved in tumor growth suppression, mainly Let-7d .

[ { "end": 27, "label": "CellLine", "start": 23, "text": "T98G" } ]

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OLE and HT may also magnify the efficacy of other types of cancer treatment.

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In nasopharyngeal cancer cell line HNE1 and HONE1, 200 μM OLE enhanced cell radiosensitivity in vitro and in vivo after injection in BALB/C nude mice, with a mechanism involving OLE-dependent removal of HIF-1α hypoxic repression exerted at miR-519d promoter region, upregulation of miR-519d, and miR-519d targeting of DNA damage-regulated protein 1 (PDRG1) .

[ { "end": 39, "label": "CellLine", "start": 35, "text": "HNE1" }, { "end": 49, "label": "CellLine", "start": 44, "text": "HONE1" }, { "end": 139, "label": "CellLine", "start": 133, "text": "BALB/C" } ]

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Despite these encouraging results, since both OLE and HT may act as transcriptional regulators and are extensively metabolized by the liver (see sections above), a careful analysis of the effects of both phenols on phase I and phase II enzyme kinetics and expression should be performed before considering the use of OLE and HT during chemotherapeutic treatments.

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Preliminary data obtained in human liver microsomes point towards OLE-mediated inhibition of CY3A and CYP1A2 activity .

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On the contrary, a study performed in 129/Sv WT and Ppara-null mice demonstrated that OLE (ingested with food, thus absorbed through the intestinal wall) stimulated the transcription of cytochrome P450 genes Cyp1a1, Cyp1a2, Cyp1b1, Cyp3a14, Cyp3a25, Cyp2c29, Cyp2c44, Cyp2d22, and Cyp2e1 in the liver, with a mechanism mediated by peroxisome proliferator-activated receptor α (PPARα) .

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Studies defining the effects of OLE and HT on the expression of and interaction with phase I and phase II enzymes are still missing, but they should be considered absolutely necessary in order to determine if OLE and HT are able to modify the metabolism of other drugs.

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Besides their possible synergic/additive actions, OLE and HT might also be seen as useful support agents during cancer treatment.

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A lot of experimental data in vivo and in vitro have definitively demonstrated the ROS scavenger ability of OLE and HT, which can also act on antioxidant cellular mechanisms restoring ROS homeostasis, including promotion of the increase in reduced glutathione levels (GSH), depletion of lipid peroxidation product malondialdehyde (MDA), intensification of the expression and/or activity of detoxicating enzymes SOD, CAT, glutathione-S-transferase (GST), and glutathione peroxidase (GSH-Px), and nuclear factor E2-related factor 2 (Nrf2) upregulation/transactivation, which in turn regulates the expression of fundamental enzymes protecting cells from oxidative damage, like HO-1 .

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Radical and non-radical ROS (including hydrogen peroxide H2O2, superoxide anion radical O2, and hydroxyl radical OH) may have a pro-tumorigenic effect; they are involved in cancer insurgence determining DNA damage, genomic instability, and interference with signalling and metabolic pathways, enhance cell proliferation through the activation of pro-survival pathways in cancer cells while promoting the reorganization of cellular antioxidant capacities and adaptation to hypoxic conditions, are involved in the development of anti-cancer therapy resistance (through the expansion of cell antioxidant capacities), push the activation of metastasis cellular programs via EMT, and boost immunosuppression and angiogenesis in the cancer microenvironment.

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However, if ROS concentration overcomes cancer cell defenses against oxidative stress and damage, or cancer cell-produced ROS balance is perturbated, ROS may account for fatal cell damage and trigger apoptosis .

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This may explain the fact that the mechanism of action of some common cancer treatments (e.g., radiation, inorganic compounds, tyrosine kinase inhibitors, monoclonal antibodies, protease inhibitors, pyrimidine analogues, alkylating agents, and anthracyclines) relies on oxidative stress and ROS-dependent apoptosis .

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OLE and HT cytotoxic actions themselves in part depend on ROS generation ; moreover, 200 μM OLE reduced HIF-1α mRNA and protein levels in HNE-1 and HONE-1 nasopharyngeal cancer cell lines , and pro-apoptotic OLE concentration corresponding to 100 μM was able to increase ROS production in MDA-MB-231 cell line, with the maximum peak obtained after 4 h incubation .

[ { "end": 143, "label": "CellLine", "start": 138, "text": "HNE-1" }, { "end": 154, "label": "CellLine", "start": 148, "text": "HONE-1" }, { "end": 299, "label": "CellLine", "start": 289, "text": "MDA-MB-231" } ]

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ROS-mediated damage at least in part accounts for chemotherapy-dependent toxicity detected at the tissue level on non-cancer cells .

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However, OLE and HT have shown an important ability to mitigate the toxicity elicited by chemotherapeutic agents mainly through their largely demonstrated antioxidant and ROS scavenger activity.

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In fact, in vivo, 50 mg/kg, 100 mg/kg, and 200 mg/kg OLE showed a dose-dependent antioxidant activity, accounting for amelioration of cisplatin-induced pancreatic, liver, lung, and stomach damage in Spraque–Dawley rats .

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In the same in vivo model of cisplatin-induced oxidative stress, 50 mg/kg, 100 mg/kg, and 200 mg/kg OLE improved anemia, thrombocytopenia, and leukopenia .

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In cyclophosphamide- and epirubicin-induced toxicity in Sprague–Dawley rats, four cycles of 150 mg/kg/week OLE reduced lipid peroxidation and increased the activity of antioxidant enzymes in heart, kidney, and liver .

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Moreover, in a model of cyclophosphamide-induced immunosuppression in broilers, a solution containing 200 mg/L HT reduced duodenal MDA levels while increasing the activity of antioxidant enzymes .

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In vitro, 50 μM and 70 μM HT reduced doxorubicin-mediated toxicity in embryonic rat cardiomyoblasts H9c2(2-1) after 48 h incubation.

[ { "end": 104, "label": "CellLine", "start": 100, "text": "H9c2" } ]

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Also, 24 and 48 h incubation with 50 μM HT reduced doxorubicin-dependent intracellular ROS accumulation, increasing SOD2 levels and protecting cells from doxorubicin-induced apoptosis .

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OLE- and HT-dependent redox homeostasis restoration might represent a potential issue with respect to OLE and HT use at nutritionally relevant concentrations as both anticancer drugs and detoxicating agents (especially during chemotherapy).

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Low concentrations of both OLE and HT (10 μM) protected HL-60 and PBMCs from H2O2-induced DNA damage, and lymphocytes from PMA-stimulated monocyte-mediated oxidative DNA damage .

[ { "end": 61, "label": "CellLine", "start": 56, "text": "HL-60" } ]

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This piece of information sounds particularly alarming, since arsenic trioxide (As2O3) is one of the agents utilized to treat acute promyelocytic leukemia, especially in combinatory first-line therapy, and its mechanism of action relies on ROS increase .

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Incubation with 30 μM HT for 48 h was not sufficient to reduce viability of Hep3B cells, but significantly improved cellular antioxidant capacities .

[ { "end": 81, "label": "CellLine", "start": 76, "text": "Hep3B" } ]

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Similarly, 5–200 μM HT was ineffective as a cytotoxic reagent, but reduced the level of oxidative stress in MCF-7 cells after 16 h incubation .

[ { "end": 113, "label": "CellLine", "start": 108, "text": "MCF-7" } ]

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Erastin is a ferropoptosis inducer that is currently under evaluation as an anti-cancer treatment .

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In ovarian carcinoma HEY cells, 100 μM OLE was not able to affect cell viability, but acted as an antioxidant, decreasing endogenous and erastin-dependent LIP and ROS levels, preventing erastin-dependent ROS accumulation in mytochondria and increasing glutathione peroxidase 4 (GPX4) levels that were reduced by erastin treatment, finally counteracting erastin-induced cell death .

[ { "end": 24, "label": "CellLine", "start": 21, "text": "HEY" } ]

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It remains to be demonstrated if nutritionally relevant and/or non-cytotoxic concentrations of OLE and HT may offer a survival advantage to neoplastic cells.

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A similar scenario has been described for other antioxidants (e.g., N-acetyl-L-cysteine, alpha-tocopherol and carotenoids), which showed a pro-tumorigenic action by exerting beneficial effects on cancer cells .

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It will be fundamental to deepen these pieces of data in order to rule out the chance that OLE and HT may promote cancer growth and metastasis.

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Another risk factor for tumorigenesis is inflammation.

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ROS imbalance itself may drive inflammation, inducing the production of pro-inflammatory cytokines interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor-α (TNF-α) .

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Persisting (chronic) or poorly controlled inflammation may directly promote tumorigenesis due to the action of ROS and the recruitment of immune cells triggering the release of growth signals and the activation of tissue repair mechanisms.

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After cancer insurgence, the production of inflammatory mediators sustained by cancer cells and surrounding actors (tissue macrophages, cancer-associated fibroblast, infiltrating immune cells, and endothelial cells, among the others) contributes to the creation of an environment favoring immune evasion, cell survival, invasion, and angiogenesis.

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Chemotherapy may also account for an exacerbation of inflammation, whose biological meaning is poorly understood, being recognized as immune-activating as well as a contributor to the failure of the therapeutic regimen .

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OLE and HT exhibit an anti-inflammatory activity that has been demonstrated in multiple in vivo and in vitro models, although some experimental variables related to the timing of administration of inflammatory stimuli might have affected the reproducibility of the results, mainly in vitro, and nutritionally relevant concentrations of OLE and HT often showed no anti-inflammatory activity on human peripheral blood mononuclear cells .

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Proof of OLE and HT modulation of inflammation in cancer cells has been obtained mostly from colorectal cancer.

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In an in vivo model of AOM/DSS-induced colorectal cancer in C57BL/6 mice, 50 mg/kg and 100 mg/kg OLE reduced IL-6, TNF-α, and IFN-γ colon tissue levels, as well as COX-2 levels .

[ { "end": 67, "label": "CellLine", "start": 60, "text": "C57BL/6" } ]

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Treatment of HCT116 and LoVo cells with 0.0154 mg/mL (≈100 μM) HT and 0.0231 mg/mL (≈150 μM) HT, respectively, for 72 h reduced phosphorylation of NF-κB p65, in turn leading to a reduction in pro-inflammatory cytokines TNF-α and IL-8 at both mRNA and protein levels.

[ { "end": 19, "label": "CellLine", "start": 13, "text": "HCT116" }, { "end": 28, "label": "CellLine", "start": 24, "text": "LoVo" } ]

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HT-dependent anti-inflammatory effect was also mediated by HT-elicited increase in protein levels of PPARγ.

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In addition, HT acted as a PPARγ agonist, promoting its transcriptional activity .

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In HT-29 cell line, 100–400 μM reduced TNF-α-induced NF-κB activation in a dose-dependent manner .

[ { "end": 8, "label": "CellLine", "start": 3, "text": "HT-29" } ]

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In in vitro models, the frame appears completely different.

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The only HT concentrations that elicited a reduction in IL-6 levels were 80 μM for HepG2 and 30 μM for Hep3B.

[ { "end": 88, "label": "CellLine", "start": 83, "text": "HepG2" }, { "end": 108, "label": "CellLine", "start": 103, "text": "Hep3B" } ]

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HT doses of 100 μM and 200 μM in HepG2 and 80 μM, 100 μM, and 200 μM in Hep3B cells produced an increase in IL-6 release .

[ { "end": 38, "label": "CellLine", "start": 33, "text": "HepG2" }, { "end": 77, "label": "CellLine", "start": 72, "text": "Hep3B" } ]

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Treatment of K562 cells with 100 μM HT produced transcriptional effects including the downregulation of IL-10 receptor and the upregulation of inflammatory mediators IL-6 and IL-8 .

[ { "end": 17, "label": "CellLine", "start": 13, "text": "K562" } ]

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OLE and HT may participate in control of cancer-associated and chemotherapy-dependent tissue inflammation by acting on non-tumor cells.

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As demonstrated in vivo, treatment of BALB/cN mice with 5, 10, and 20 mg/kg OLE suppressed signs of cisplatin-induced renal inflammation, including tissue modulation of TNF-α levels .

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Four cycles of 150 mg/kg/week OLE in Sprague–Dawley rats reduced serum TNF-α and IL-6 in an experimental model of epirubicin and cyclophosphamide toxicity .

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In a model of cyclophosphamide-induced immunosuppression in broilers, a solution containing 200 mg/L HT promoted the duodenal expression of anti-inflammatory cytokines IL-4 and IL-10 .

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It remains to be assessed if such a modulatory activity is able to contribute to the immunosuppressant environment surrounding cancer cells.

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From the analysis of the literature reported in this review, it becomes evident that the multifaceted nature of OLE and HT interaction with molecular mediators in cancer cells and non-cancer tissues determines the need for safe strategies to improve OLE and HT bioavailability and delivery, also offering a more stable and highly selective anti-proliferative activity throughout time.

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