Mechanism of apoptosis in HL-60 cells induced by n-3 and n-6 polyunsaturated fatty acids 1 1Abbreviations: AA, arachidonic acid; CsA, cyclosporin A; Cyt.c, cytochrome c; DCFH-DA, 2′,7′-dichlorofluorescein diacetate; DPA, docosapentaenoic acid; EPA, eicosapentaenoic acid; HE, hydroethidine; JC-1, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazol carbocyanine iodide; MPT, membrane permeability transition; PUFA, polyunsaturated fatty acid; ROS, reactive oxygen species; and z-VAD-fmk, z-Val-Ala-Asp(OMe)-f

Arita, Kayo; Kobuchi, Hirotsugu; Utsumi, Toshihiko; Takehara, Yoshiki; Akiyama, Jitsuo; Horton, Alan A.; Utsumi, Kozo

doi:10.1016/s0006-2952(01)00723-7

Cited by 101 publications

(11 citation statements)

References 39 publications

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“…It was also reported that treatment of HL-60 cells with EPA results in caspases 3, 6, 8 and 9 activation, Bid cleavage, and cytochorme c release [33]. The results of our present study using annexin-V/PI double staining and TUNEL assay confirmed that DHA can induce apoptosis both in vitro and in vivo ( Fig.…”

Section: Discussionsupporting

confidence: 87%

Docosahexaenoic Acid Induces Apoptosis in MCF-7 Cells In Vitro and In Vivo via Reactive Oxygen Species Formation and Caspase 8 Activation

et al. 2010

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BackgroundThe present study sought to further investigate the in vitro and in vivo anticancer effects of a representative omega-3 fatty acid, docosahexaenoic acid (DHA), with a focus on assessing the induction of oxidative stress and apoptosis as an important mechanism for its anticancer actions.Methodology/Principal Findings In vitro studies showed that DHA strongly reduces the viability and DNA synthesis of MCF-7 human breast cancer cells in culture, and also promotes cell death via apoptosis. Mechanistically, accumulation of reactive oxygen species and activation of caspase 8 contribute critically to the induction of apoptotic cell death. Co-presence of antioxidants or selective inhibition or knockdown of caspase 8 each effectively abrogates the cytotoxic effect of DHA. Using athymic nude mice as an in vivo model, we found that feeding animals the 5% fish oil-supplemented diet for 6 weeks significantly reduces the growth of MCF-7 human breast cancer cells in vivo through inhibition of cancer cell proliferation as well as promotion of cell death. Using 3-nitrotyrosine as a parameter, we confirmed that the fish oil-supplemented diet significantly increases oxidative stress in tumor cells in vivo. Analysis of fatty acid content in plasma and tissues showed that feeding animals a 5% fish oil diet increases the levels of DHA and eicosapentaenoic acid in both normal and tumorous mammary tissues by 329% and 300%, respectively.Conclusions/SignificanceDHA can strongly induce apoptosis in human MCF-7 breast cancer cells both in vitro and in vivo. The induction of apoptosis in these cells is selectively mediated via caspase 8 activation. These observations call for further studies to assess the effectiveness of fish oil as a dietary supplement in the prevention and treatment of human breast cancer.

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Section: Discussionsupporting

confidence: 87%

Docosahexaenoic Acid Induces Apoptosis in MCF-7 Cells In Vitro and In Vivo via Reactive Oxygen Species Formation and Caspase 8 Activation

et al. 2010

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“…In addition, it has been reported that EPA treatment in vitro [17, 45, 46] and FO supplementation in vivo [47, 48] could increase ROS and Ca 2+ levels in mitochondria and disrupt mitochondrial membrane potential leading to cell apoptosis in various human and rat cancer cells. To investigate whether the pro-apoptotic effect of EPA and krill oil extract in the present study was through mitochondrial pathway, we evaluated the changes in MMP after 48 h of treatment.…”

Section: Discussionmentioning

confidence: 99%

Krill oil extract suppresses cell growth and induces apoptosis of human colorectal cancer cells

Jayathilake

Senior

2016

BMC Complement Altern Med

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BackgroundColorectal cancer (CRC) is the third most common cancer in the world. The current available treatments for CRC include surgery, chemotherapy and radiotherapy. However, surgery is only useful when the disease is diagnosed at the earlier stage. Chemotherapy and radiotherapy are associated with numerous side effects that decrease the patients’ quality of life. Safer, effective alternatives, such as natural compounds, to chemotherapy are desirable. This study assessed the efficacy of free fatty acid (FFA) extract of krill oil on three human CRC cells lines.MethodsHCT-15, SW-480 and Caco-2 cells were treated with the FFA extracts of krill oil and fish oil for 48 h while treatments with the bioactive omega-3 polyunsaturated fatty acids (LC n-3 PUFA) of these marine oils, eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) in comparison with a n-6 PUFA, arachnoid acid (AA, C20:4n-6) were up to 72 h at the concentrations of 50, 100, 150 and 200 μM. Effects of all the treatments on cell proliferation were assessed using a water-soluble tetrazolium-1 (WST-1) assay kit at 24, 48 and 72 h. Effects of FFA extract of krill oil and EPA on apoptosis and mitochondrial membrane potential were determined using commercial kits after 48 h of treatment.ResultsKrill oil extract inhibited cell proliferation of all three cell lines in the similar manner as fish oil extract. A significant cell apoptosis and increase in mitochondrial membrane potential were observed after the treatment with krill oil extract. EPA at the concentration of 200 μM reduced significantly the proliferation of HCT-15 and SW-480 at 24, 48 and 72 h. In addition, EPA treatment (100 and 200 μM) resulted in significant cell apoptosis in all three cell lines. No significant changes were observed after treatment with DHA and AA.ConclusionsOur results indicate that the FFA extract of krill oil maybe an effective chemotherapeutic agent to suppress proliferation and induce apoptosis in CRC cells through its bioactive constitute EPA. Although the exact mechanism of the pro-apoptotic properties of krill oil extract is unclear, mitochondrial pathway seems to be implicated.

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“…However, recent studies demonstrated that this is not always the case, and activation of ERK could actually cause apoptosis or growth arrest (25–28). At higher doses, n-3 PUFAs have been reported to induce the production of reactive oxygen species (ROS) (29) and c-jun N-terminal kinase (JNK) phosphorylation and induce apoptosis (30) or growth arrest (19). …”

Section: Introductionmentioning

confidence: 99%

Omega-3 polyunsaturated fatty acids selectively inhibit growth in neoplastic oral keratinocytes by differentially activating ERK1/2

Nikolakopoulou¹,

Nteliopoulos

Michael‐Titus

et al. 2013

Carcinogenesis

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The long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs)—eicosapentaenoic acid (EPA) and its metabolite docosahexaenoic acid (DHA)—inhibit cancer formation in vivo, but their mechanism of action is unclear. Extracellular signal-regulated kinase 1/2 (ERK1/2) activation and inhibition have both been associated with the induction of tumour cell apoptosis by n-3 PUFAs. We show here that low doses of EPA, in particular, inhibited the growth of premalignant and malignant keratinocytes more than the growth of normal counterparts by a combination of cell cycle arrest and apoptosis. The growth inhibition of the oral squamous cell carcinoma (SCC) lines, but not normal keratinocytes, by both n-3 PUFAs was associated with epidermal growth factor receptor (EGFR) autophosphorylation, a sustained phosphorylation of ERK1/2 and its downstream target p90RSK but not with phosphorylation of the PI3 kinase target Akt. Inhibition of EGFR with either the EGFR kinase inhibitor AG1478 or an EGFR-blocking antibody inhibited ERK1/2 phosphorylation, and the blocking antibody partially antagonized growth inhibition by EPA but not by DHA. DHA generated more reactive oxygen species and activated more c-jun N-terminal kinase than EPA, potentially explaining its increased toxicity to normal keratinocytes. Our results show that, in part, EPA specifically inhibits SCC growth and development by creating a sustained signalling imbalance to amplify the EGFR/ERK/p90RSK pathway in neoplastic keratinocytes to a supraoptimal level, supporting the chemopreventive potential of EPA, whose toxicity to normal cells might be reduced further by blocking its metabolism to DHA. Furthermore, ERK1/2 phosphorylation may have potential as a biomarker of n-3 PUFA function in vivo.

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Cited by 101 publications

References 39 publications

Docosahexaenoic Acid Induces Apoptosis in MCF-7 Cells In Vitro and In Vivo via Reactive Oxygen Species Formation and Caspase 8 Activation

Docosahexaenoic Acid Induces Apoptosis in MCF-7 Cells In Vitro and In Vivo via Reactive Oxygen Species Formation and Caspase 8 Activation

Krill oil extract suppresses cell growth and induces apoptosis of human colorectal cancer cells

Omega-3 polyunsaturated fatty acids selectively inhibit growth in neoplastic oral keratinocytes by differentially activating ERK1/2

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