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 Table of Contents  
REVIEW
Year : 2017  |  Volume : 3  |  Issue : 3  |  Page : 80-86

Fish oil and prostate cancer: Effects and clinical relevance


Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

Date of Submission16-Nov-2016
Date of Acceptance10-Mar-2017
Date of Web Publication8-Jun-2017

Correspondence Address:
Pei Liang
Department of Urology, University of California, P.O. Box 951738, Los Angeles, CA 90095-1738
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_63_16

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  Abstract 

Men who intake high ratios of fish oil or omega-3 fatty acids (FAs), especially docosahexaenoic acid and eicosapentaenoic acid, relative to omega-6 arachidonic acid have been found to have a decreased risk of prostate cancer compared to those with low ratios in some but not all case-control and cohort studies. Primary prevention trials with either risk biomarkers or cancer incidence as endpoints regarding the association between omega-3 FA consumption and risk of prostate cancer are studded with controversial results. However, many clinical trials have shown that fish oil could decrease the risk of developing prostate cancer. The anticancer properties of anticancer drugs could be greatly improved when combined with fish oil. We briefly reviewed fish oil and relevant omega-3 FAs as well as early investigations in prostate cancer prevention and treatment.

Keywords: Docosahexaenoic acid, fish oil, omega-3 fatty acids, prostate cancer


How to cite this article:
Liang P, Gao M. Fish oil and prostate cancer: Effects and clinical relevance. Cancer Transl Med 2017;3:80-6

How to cite this URL:
Liang P, Gao M. Fish oil and prostate cancer: Effects and clinical relevance. Cancer Transl Med [serial online] 2017 [cited 2017 Aug 19];3:80-6. Available from: http://www.cancertm.com/text.asp?2017/3/3/80/207620


  Introduction Top


Prostate cancer is a disease in which malignant (cancer) cells form in the tissues of the prostate, a small walnut-shaped gland that produces the seminal fluid that nourishes and transports sperm. It is the second most common cancer found in men after skin cancer. In the United States, approximately 1 of 7 men is diagnosed with prostate cancer. Age and race can affect the incidence rate of prostate cancer. Prostate cancer is very uncommon in men younger than 45 years old, and it becomes more common in older age groups. The average age at which people are diagnosed with prostate cancer is 70 years old.[1] Prostate cancer occurs about 60% more often in African-American men than in Caucasian American men, and it is also more likely to be in an advanced stage when diagnosed.[2],[3] Another factor that affects prostate cancer is diet. Research suggests that high dietary fat may contribute to an increased risk of developing prostate cancer.[4] The disease is much more common in countries where meat and dairy products are dietary staples compared to countries where the basic diet consists of rice, soybean products, and vegetables.[5] For example, Japanese and African males living in their native countries have a low incidence of prostate cancer.[6] In addition, several epidemiological studies have indicated that high fish consumption is correlated with the low incidence of prostate cancer.[7],[8] The major active constituent of these marine-based foods is fish oil, which performs the anticancer role. Fish oil can be obtained from by eating fish, including mackerel, herring, tuna, salmon, cod liver, whale blubber, and seal blubber as well as fish oil supplements. The components of fish oil that are beneficial to human body are known as omega-3 fatty acids (FAs) which are primary structural components of human brain, cerebral cortex, retina, sperm, testes, and skin. Two of the most important of these omega-3 FAs contained in fish oil are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). DHA has the longest and most unsaturated FA chain and is part of an important family of compounds that is reputed to possess many human health benefits, including anticancer properties.[1],[9] The aim of this review is to assess the most recent studies of fish oil on its therapeutic role against prostate cancer as well as ongoing and recruited clinical trials. The role of fish oil in combination with different anticancer therapies to enhance drug efficacy in chemotherapy will also be discussed.


  Fatty Acids Top


Foods high in omega-3 FAs include salmon, halibut, sardines, albacore, trout, herring, walnut, flaxseed oil, and canola oil. Other foods that contain omega-3 FAs include shrimp, clams, light chunk tuna, cat fish, cod, and spinach. Omega-6 FAs are a class of essential polyunsaturated FAs (PUFAs) with the initial double bond at the sixth carbon position from the methyl group (hence the “6”). Examples of foods rich in omega-6 FAs include corn, safflower, sunflower, soybean, and cotton seed oil. In the US, the intake of linoleic acid (LA; n-6) is on the order of 10–20 g/day, thus constituting 85% of the total FAs consumed.[10] In contrast, the n-3 FAs, EPA and DHA, are contained in fish oils and are the major FAs consumed in the Japanese diet. The ratio of long-chain omega-6 to omega-3 FAs in Western diets ranges from 10:1 to 20–25:1, whereas in Japan this ratio is 4:1.[11] Although the ideal total omega-3:omega-6 intake ratio has not been defined, a ratio approaching 1:1 or 1:2 similar to that of precivilized man is generally accepted as associated with a low incidence of diseases characterized by chronic inflammation and therefore is desirable.[12],[13] Fish oil is obtained from the livers of lean fish (e.g., cod liver) or the flesh of oily fish (e.g., tuna). A 1 g fish oil capsule will provide about 0.3 g of EPA and DHA. This means that EPA and DHA combined comprises about 30% of the FAs present in a typical fish oil supplement. Other pharmaceutical grade, highly concentrated fish oil supplements are also available. In fish and traditional fish oil supplements, most of the FAs are present as components of triacylglycerols. The other forms of EPA and DHA are phospholipids, which the omega-3 FAs are prepared from krill oil. DHA and EPA can be synthesized from simpler plant-derived n-3 FAs [Figure 1], but this metabolic pathway does not appear to be very efficient in many humans.[14] The major omega-6 FA is arachidonic acid (ARA), which is synthesized from simpler plant-derived omega-6 FAs in a pathway that competes with the synthesis of EPA [Figure 1].
Figure 1: Biosynthesis n-6 and n-3 fatty acids

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  Fish Oil and Prostate Cancer Top


Fish oil has been used for the prevention and treatment of prostate cancer. Epidemiologic studies found that a low-fat diet combined with a high intake of fish and marine-derived omega-3 FAs prevented the development and progression of prostate cancer.[15] Conversely, a high-fat diet rich in omega-6 FAs promoted prostate cancer.In vitro studies have demonstrated DHA's role in inhibiting cancer cell proliferation and invasion.[16],[17],[18],[19],[20],[21] In vivo studies on fish oil and DHA in animals have also described their properties as anticancer agents.[22],[23],[24],[25],[26],[27],[28],[29],[30],[31] In addition to strong in vivo and in vitro studies, clinical trials have also suggested fish oil's role in decreasing the risk of cancer development and progression.[32],[33],[34] As shown in [Table 1], these studies were conducted using fish oil for inhibiting tumor growth in vitro and animals as well as clinical trials in prostate cancer.
Table 1: Effects of fish oil in prostate cancer

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In vitro studies

DHA has been reported to inhibit hormone-dependent growth of LNCaP prostate cancer cells by reducing protein expression level of the androgen receptor (AR).[20] In this study, it was demonstrated that DHA exhibits no effect on the translation process of the AR, but promotes the proteasome-mediated degradation of the AR, and subsequently represses the expression of androgen-related genes.[20] Liu et al.[35] reported in 2014 that EPA and DHA inhibited proliferation of DU145 cells in response to lysophosphatidic acid (LPA) and suppressed LPA-induced activating phosphorylations of ERK, FAK, and p70S6K, as well as expression of the matricellular protein CCN1. Another two studies using marine- and plant-derived omega-3 FAs to inhibit prostate cancer growth reported that different trends of inhibition of PC-3 cell proliferation were observed for three omega-3 PUFAs: DHA, EPA, and α-linolenic acid (ALA). Their results showed that DHA had the most pronounced effects on cell proliferation, while ALA had the least effect among the three omega-3 PUFAs.[36],[37] Furthermore, all three of the omega-3 PUFAs regulated genes involved in inflammation, cell cycle, and apoptosis. In addition, Li et al.[38] investigated the effects of EPA and DHA on modulating of migration and invasion of prostate cancer cells induced by TAMs-like M2-type macrophages. In this study, PC-3 prostate cancer cells were pretreated with EPA, DHA, or the peroxisome proliferator-activated receptor (PPAR)-γ antagonist, GW9662, before exposure to conditioned medium which was derived from M2-polarized THP-1 macrophages. Their data showed that EPA/DHA administration decreased migration, invasion, and macrophage chemotaxis of PC-3 cells induced by TAM-like M2-type macrophages, which may partly be explained by activation of PPAR-γ and decreased NF-kB p65 transcriptional activity.

In vivo study

As early as 1987, Karmali et al.[39] conducted a study to determine if DHA and EPA can modify the growth of DU-145 human prostatic tumor cells in nude mice. Two experimental diets tested contained either 23.52% corn oil or 20.52% fish oil plus 3% corn oil (w/w). The fish oil-fed group of mice displayed significantly inhibited tumor growth. Tumor cells in histological sections were smaller, but more connective tissue was present. In addition, immunochemical staining for human prostatic acid phosphatase was less intense, and tumor content of prostaglandin E2 was smaller than in the 23.52% corn oil-fed group. Another study on the athymic mouse xenograft model simulating radical prostatectomy also examined the roles that FAs play in prostate cancer.[40] To study whether the protumorigenic role of 15-LO-1 and dietaryomega-6 LA can be modulated by altering omega-3 levels through diet, tumors formed from LAPC-4 cells were surgically removed (the mouse model is to simulate a radical prostatectomy). Mice were then randomly divided into three different diet groups: high omega-6 LA, high omega-3 stearidonic acid (SDA), and no fat, and the effects of omega-6 and omega-3 FAs in the diet on LAPC-4 tumor recurrence by monitoring for prostate-specific antigen (PSA) were examined. The results showed that prostate tumors can be modulated by the manipulation of omega-6 and omega-3 ratios through diet and that the omega-3 FA SDA (precursor of EPA) promotes apoptosis and decreases proliferation in cancer cells, causing decreased PSA doubling time, compared to omega-6 LA FA. Berquin et al.[41] further determined the influence of FAs on prostate cancer risk in animals with a defined genetic lesion. They used prostate-specific Pten-knockout mice, an immune-competent, orthotopic prostate cancer model, and diets with defined PUFA levels. The results showed that omega-3 FAs reduced prostate tumor growth, slowed histopathological progression, and increased survival, whereas omega-6 FAs had the opposite effect. Introducing an omega-3 desaturase, which converts omega-6 to omega-3 FAs, into the Pten-knockout mice also reduced tumor growth similar to the omega-3 diet. In another androgen-sensitive mouse prostate cancer allograft model, murine MycCaP tumor cells were grown in fully immunocompetent FVB mice to study the effect of high-fat fish oil (omega-3) or corn oil (omega-6) diet on prostate cancer tumor growth.[31] This model offers several advantages in studying this issue. First, the immunocompetent environment of this model enables the examination of both adaptive and innate arms of the immune system in prostate cancer progression.[52],[53] Second, macrophages comprise a significant component of the tumor microenvironment in implanted Myc-CaP tumors. The results showed that tumor volumes were significantly smaller in mice in the omega-3 versus the omega-6 group. In addition, both M1 and M2 macrophages, as well as associated cytokines and chemokines, were also lower in the omega-3 group. The results of these studies clearly showed that fish oil can inhibit prostate cancer development and progression in different animal models.

Clinical trials

Although animal studies support an inverse association between marine-derived-3 FA intake and the prostate cancer risk, the history of clinical trials regarding the association between omega-3 FA consumption and risk of prostate cancer is studded with controversial results.[54],[55] In 1999, Norrish et al.[42] examined the relationship between prostate cancer risk and both EPA and DHA in erythrocyte biomarkers in a population-based case-control study involving 317 prostate cancer cases. They found that reduced prostate cancer risk was associated with high erythrocyte phosphatidylcholine levels of EPA and DHA. These data were confirmed by other works with a long-term follow-up, in which an increasing proportion of fish in the diet was associated with a decreasing frequency of prostate cancer, especially for metastatic cancers.[43],[44],[45] Later, case-control and cohort studies suggested that an increased intake of fish was associated with decreased prostate cancer mortality.[8],[46] However, the relationship between omega-3 FA levels and prostate cancer risk is varied. Some studies have shown no association between the two,[46],[47] while two other studies have even demonstrated a positive association with high grade prostate cancer.[48],[49] In the first work, inflammation-related phospholipid FAs and the 7-year-period prevalence of prostate cancer in a nested case-control analysis of participants was examined in prostate cancer prevention trial. Phospholipid FAs were extracted from serum, and concentrations of omega-3, omega-6, and trans-FAs were expressed as proportions of the total. The findings of this study are contrary to those expected from the pro- and anti-inflammatory effects of these FAs and suggested that DHA was positively associated with high-grade disease. The second study measured the FA composition of plasma phospholipids and found that there were significant positive associations between myristic, alpha-linolenic, and EPA with risk of high-grade prostate cancer. This reflects differences in intake or metabolism of these FAs between the precancer cases and controls. All of these clinical trials suggest a greater complexity of effects of these nutrients with regard to prostate cancer risk.

Fish oil and anticancer drugs in prostate cancer

Although fish oil itself has been shown to possess anticancer properties against prostate cancer both in vitro and in animal models, it has not been successfully used to treat cancer patients in clinical trials. However, evidence strongly suggests that fish oil intake, combined with different anticancer therapies, will enhance drug efficacy.

Arsenic trioxide (As2O3), an inorganic compound, has long been of biomedical interest and used to treat cancer. In the 1970s, As2O3 was first used by the Chinese researcher Tingdong Zhang for the treatment of acute promyelocytic leukemia (APL). The treatment has been very successful clinically. It has dual effects on APL cells. At higher concentrations (1–2 μm/L), it induces programmed cell death or apoptosis of the leukemic cells due to an accumulation of intracellular reactive oxygen species. This in turn disrupts the mitochondrial membrane potential, the release of cytochromes with elevation of caspase-3 and other caspases activity, as well as the decline of Bcl-2 expression.[56],[57],[58],[59] At lower concentration (0.1–0.5 μm/L), As2O3 triggers differentiation with elevation of CD11b expression accompanied by morphologically partial differentiation.[60] However, the benefits of using As2O3 in treating solid tumors are limited because the concentrations used in these tumors are 10 times higher, which generally causes toxic side effects.[58],[61],[63],[64] Therefore, As2O3 should be used in combination with other drugs or nutrients such as fish oil to increase its effectiveness as an approach to treat solid tumors.

Baumgartner et al.[49] found that DHA (25 μm) strongly increases As2O3(1 μm)-mediated apoptosis in the androgen-independent prostate cancer cell line PC-3 that is typically resistant to clinically achievable concentrations of 1 μm As2O3, whereas individual treatment with either As2O3 or DHA at this concentration only slightly increased the percentage of apoptotic cells. The authors then addressed the effect of using combined As2O3/DHA treatment on the content of intracellular lipid peroxidation products (thiobarbituric acid-reactive substances [TBARSs]). There is a strong positive correlation between the intracellular TBARS content and the percentage of apoptotic cells upon treatment with As2O3 and DHA. These findings suggest that the combination of As2O3 and DHA may be especially effective in prostate cancer cells in increasing the sensitivity of prostate cancer cells toward As2O3. Further investigations on the combination of As2O3 and DHA in prostate cancer treatment are therefore clearly warranted.

1a,25-dihydroxyvitamin D3 (1a,25(OH)2D3) is a hormonally active form of Vitamin D3 in calcium absorption and deposition. It has widespread effects on cellular differentiation and proliferation, and can modulate immune responsiveness, as well as central nervous system function.[65],[66],[67],[68] It has also been shown that this hormone promotes cellular differentiation and inhibits the proliferation and invasive potential of a number of different cancers including breast, prostate, and other carcinomas in vitro and in vivo.[69],[70],[71],[72],[73],[74],[75] However, the use of high levels of 1a,25(OH)2D3 may result in hypercalcemia. The combined effects of 1a,25(OH)2D3 and fish oil have been observed to decrease the risk of hypercalcemia due to a lower concentration of 1a,25(OH)2D3 given in the medication. Therefore, increasing the sensitivity of 1a,25(OH)2D3 while lowering its concentration is critical to decreasing the risk of hypercalcemia. Istfan et al.[50] reported that in testing prostate cancer cells, LNCaP-c115, a high passage androgen-independent cell line, with 1a,25(OH)2D3 and fish oil, synergistically inhibited more G1/S-phase transition than with each treatment individually. This study provided the important mechanistic information necessary for the design of human and clinical studies to help improve the mortality and morbidity rates associated with prostate cancer.


  Possible Mechanism of Anticancer Effect of Fish Oil Top


There have been a number of proposed mechanisms by which fish-derived omega-3 FAs may influence prostate cancer risk or progression [Figure 2], and the prevailing hypothesis is that metabolites of omega-3 FAs are responsible for the anticancer effects. It is known that uptake of omega-3 FAs modifies membrane phospholipid composition in a manner that decreases production of ARA (omega-6)-derived eicosanoids that are proinflammatory [76] and increases n-3 metabolites (e.g., “resolvins”) that are anti-inflammatory.[77] The other mechanism is that omega-3 FAs can induce apoptosis in human prostate cancer cells by activating the nuclear receptor PPAR-γ and upregulating the PPAR-γ target gene, syndecan-1 (SDC-1).[78] It has been suggested that omega-3 FAs induced apoptosis in prostate cancer by suppression of SDC-1-dependent phosphorylation of PDK1/Akt/Bad. Recently, another mechanism reported that DHA can activate G-protein-coupled receptors, GPR120. The researchers found that GPR120 functions as an n-3 PUFA receptor in vitro and in vivo and suggested that diminished activation of GPR120 can be an important contributor to tissue inflammation.[79],[80]
Figure 2: Signaling pathways of omega-3 fatty acids exert anticancer effect

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  Conclusion Top


The evidence from in vitro and preclinical studies indicates that fish oil, especially DHA and EPA, is a natural substance that can be favorably used for prevention and treatment of prostate cancer. The decreased side effects of anticancer drugs when combined with fish oil could increase prostate cancer patients' health and improve their quality of life. However, more patient-based clinical trials are needed to implement fish oil for regular use by prostate cancer patients.

Financial support and sponsorship

This work was supported by the Department of Defense Prostate Cancer Research Program (PC141593 to PL).

Conflicts of interest

There are no conflicts of interest.

 
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