Saffron-Based Crocin Prevents Early Lesions of Liver Cancer: In vivo, In vitro and Network Analyses

Amin, Amr; Hamza, Alaaeldin Ahmed; Daoud, Sayel; Khazanehdari, Kamal; Hrout, Ala’a Al; Baig, Badriya; Chaiboonchoe, Amphun; Adrian, Thomas E.; Zaki, Nazar; Salehi‐Ashtiani, Kourosh

doi:10.2174/1574892810666151102110248

Cited by 70 publications

(41 citation statements)

References 53 publications

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“…Administration of GSE to DEN-2AAF-treated rats in this work counteracted DEN-2AAF-induced oxidative stress as shown by the restoration of antioxidant levels of SOD and CAT in the liver and the diminishing of important markers of oxidative stress, such as MDA and P.Carbonyl. DEN-2AAF-induced CAT activity has been similarly shown to be increased in cancer cells, most likely, to favor cell proliferation by inducing genetic instability and activation of oncogenes 6 , 34 . The prevention of oxidative stress by GSE might be attributed to its potent antioxidant capacity that was confirmed in this study.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of the grape seeds extract’s effect against chemically induced liver cancer: In vivo and in vitro analyses

Hamza

Heeba

Elwy

et al. 2018

Sci Rep

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The purpose of this study was to investigate the anti-cancer property of grape seed extract (GSE) during early stages of developing liver cancer using a two-stage carcinogenic model combining diethylnitrosamine (DEN) and 2-Acetyl Aminofluorene (2-AAF). Administration of GSE at doses 25, 50 and 100 mg/kg per day started at the beginning of promotion periods and continued for 14 weeks. GSE dramatically inhibited pre-neoplastic foci formation as well as significantly decreased the number and the area of placental glutathione-S-transferase in livers of DEN-2AAF-treated rats by approximately 4 & 10 fold deductions, respectively. GSE's effects were associated with induced apoptosis, reduced cell proliferation, decreased oxidative stress and down regulation of histone deacetylase activity and inflammation makers, such as cyclooxygenase 2, inducible nitric oxide synthase, nuclear factor-kappa B-p65 and p-phosphorylated tumor necrosis factor receptor expressions in liver. GSE treatment also decreased the viability of HepG2 cells and induced early and late apoptosis through activating caspase-3 and Bax. Furthermore, GSE induced G2/M and G1/S cell cycle arrest. The present study provides evidence that the GSE's anticancer effect is mediated through the inhibition of cell proliferation, induction of apoptosis, modulating oxidative damage and suppressing inflammatory response.Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death both in developed and under-developed countries 1 . Chronic infection with hepatitis B and C are the main causes of HCC 2 . Other factors that contribute to the formation of HCC include fatty liver disease, iron overload, alcoholism and exposure to environmental carcinogens 3 . One of the most common carcinogens is diethylnitrosamine (DEN), which is widely used in the surrounding of everyday life, in tobacco, smoke, processed food, gasoline, and cosmetics 4 .Chemoprevention of cancer especially by natural compounds is a promising strategy to protect against various stages of cancer development [5][6][7] . Total plant extracts have been of a particular interest mainly because of the synergistic effects of the cocktail of plant metabolites and their multiple points of intervention during chemoprevention 7,8 . The development of pre-neoplastic foci of altered hepatocytes (FAH) was exploited as short-term bioassays to assess the chemopreventive potential of natural products against cancer formation 9 . Thus, inhibiting or suppressing the development of pre-neoplastic FAH by natural products may lead to diminishing the subsequent progression to liver cancer. One particular plant product that has gained much attention is grape seed extract (GSE). Grapes (Vitis vinifera) are rich in polyphenols, with 60-70% of grape polyphenols being found in the seeds, which are available as a nutraceutical agent. The consumer's interest in GSE has been primarily due to its high content of antioxidants in the form of flavonoids, polyphenols and proanthocyanidins 10,11 . GSE has been shown to posses...

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Section: Discussionmentioning

confidence: 99%

Molecular characterization of the grape seeds extract’s effect against chemically induced liver cancer: In vivo and in vitro analyses

Hamza

Heeba

Elwy

et al. 2018

Sci Rep

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“…[9][10][11][12][13] There are already studies showing the therapeutic value of crocin as anticonvulsant, antiinflammatory, antidepressant and antitumor molecule. [9][10][11][12][13] There are already studies showing the therapeutic value of crocin as anticonvulsant, antiinflammatory, antidepressant and antitumor molecule.…”

Section: Introductionmentioning

confidence: 99%

Crocin synergistically enhances the antiproliferative activity of 5‐flurouracil through Wnt/PI3K pathway in a mouse model of colitis‐associated colorectal cancer

Amerizadeh

Rezaei

Rahmani

et al. 2018

J of Cellular Biochemistry

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Colorectal cancer (CRC) is the third most common cause of cancer-related death, and hence there is a need for the identification of novel-agents to improve the efficacy of existing therapies. There is growing evidence for the antitumor activity of crocin, although its activity and molecular mechanisms in CRC remains to be elucidated. Here we explored the therapeutic application of crocin or its combination with 5-flurouracil in a mouse model of colitis-associated colon cancer. The antiproliferative activity of crocin was assessed in two-dimensional and three-dimensional cell-culture models. The migratory behaviors were determined, while the expression levels of several genes were assessed by quantitative reverse transcriptase polymerase chain reaction/Western blot analysis. We examined the anti-inflammatory properties of crocin by pathological evaluation and disease-activity index as well as oxidative or antioxidant markers: malondialdehyde (MDA) and total-thiols (T-SH) levels and superoxide dismutase (SOD) and catalase (CAT) activity. Crocin suppressed cell-growth and the invasive behavior of CRC cells through modulation of the Wnt-pathway and E-cadherin. Moreover, administration of crocin alone, or in combination with 5-FU dramatically reduced the tumor number and tumor size in both distal/mid-colon followed by reduction in disease-activity index. Crocin also suppressed the colonic inflammation induced by dextran-sulfate-sodium and notably recovered the increased levels of MDA, decreased thiol levels and activity of CAT levels. Crocin was able to ameliorate the severe inflammation with mucosal ulcers and high-grade dysplastic crypts as detected by inflammation score, crypt loss, pathological changes and histology scores. We demonstrated an antitumor activity of crocin in CRC and its potential role in improvement of inflammation with mucosal ulcers and high-grade dysplastic crypts, supporting the desireability of further investigations on the therapeutic potential of this approach in CRC.

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“…Studies have shown that crocin exhibits protective roles in liver diseases. Crocin not only prevents early liver damages of liver cancer 21 , 22 but it also directly suppresses cell survival in HCC by targeting different downstream effectors to inhibit proliferation and induce apoptosis. 13 Considering the important roles of autophagy in cell homeostasis, here, we explored its roles in crocin-associated apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Crocin induces autophagic apoptosis in hepatocellular carcinoma by inhibiting Akt/mTOR activity

Yan¹,

Liu²,

Qian³

et al. 2018

OTT

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BackgroundAutophagy induction is a common mechanism for antitumor chemicals in induction of cancer cell death. However, the role of autophagy in crocin-induced apoptosis is barely studied in hepatocellular carcinoma (HCC).Materials and methodsThe influence of crocin on growth, apoptosis, and autophagy and its mutual relations were analyzed by Cell Counting Kit-8 assay, flow cytometer, EGFP-LC3 puncta analysis, and Western blot in HCC cells. The activities of Akt/mTOR axis and its roles in autophagy regulation were also detected by Western blot in HCC cells treated with crocin. Finally, the roles of Akt/mTOR axis in crocin-induced autophagic apoptosis were analyzed by Western blot and flow cytometer in HCC cells.ResultsThe results showed that crocin can induce growth inhibition in a does- and time-dependent pattern by apoptosis. Increased LC3 puncta and upregulated LC3-II accumulation was observed as early as at 6 hours in HepG2 and HCCLM3 cells treated with 3 mg/mL crocin. Moreover, apoptosis analysis using flow cytometer and cleaved poly (ADP-ribose) polymerase detection revealed that autophagy initiation was prior to apoptosis activation in HCC cells treated with crocin. When autophagy was blocked with 3-methyladenine, crocin-induced apoptosis was inhibited in HCC cells. Furthermore, crocin treatment constrained the activities of key proteins in Akt/mTOR signaling, such as p-Akt (S473), p-mTOR (S2448), and p-p70S6K (T389), suggesting that crocin could induce autophagic apoptosis in HCC cells in an Akt/mTOR-dependent mechanism. Indeed, when autophagy was suppressed by forced expression of Akt, the crocin-induced apoptosis was also impaired in HCC cells.ConclusionThe results suggested that crocin could induce autophagic apoptosis in HCC cells by inhibiting Akt/mTOR activity. This study originally revealed that autophagic apoptosis is a novel cytotoxic function of crocin, which lays the theoretical foundation for clinical application of crocin in HCC.

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Saffron-Based Crocin Prevents Early Lesions of Liver Cancer: In vivo, In vitro and Network Analyses

Abstract: Taken together, our findings introduce crocin as a candidate chemopreventive agent against HCC.

Cited by 70 publications

References 53 publications

Molecular characterization of the grape seeds extract’s effect against chemically induced liver cancer: In vivo and in vitro analyses

Molecular characterization of the grape seeds extract’s effect against chemically induced liver cancer: In vivo and in vitro analyses

Crocin synergistically enhances the antiproliferative activity of 5‐flurouracil through Wnt/PI3K pathway in a mouse model of colitis‐associated colorectal cancer

Crocin induces autophagic apoptosis in hepatocellular carcinoma by inhibiting Akt/mTOR activity

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