The Pharmacological Effect of Omega-3 Fatty Acids Prevent Cancer Progression in Colon and Breast Cancer

Abstract

Breast cancer and colon cancer are the common cancers in the world. Dietary fatty acids, n-3 polyunsaturated fatty acids (PUFAs), are believed to play an important role in preventing cancers. Studies have shown that long-chain n-3 PUFAs, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are able to inhibit and prevent cancers. The present review evaluates DHA and EPA the role in the prevention of breast cancer and colon cancer. Further, anticancer mechanisms of action of DHA and EPA are also examined.

Method: This review gathers the information from electronic and scientific literature database such as Pubmed, and Science Direct and so on. In this review, we focus on the pharmacological effects of DHA and EPA in breast cancer and colon cancer.

Conclusion: This review suggests that n-3 PUFAs have anticancer effects and beneficial to human health.

Keywords: n-3 Polyunsaturated Fatty Acids (PUFAs); Docosahexaenoic Acid (DHA); Breast Cancer; Colon Cancer

Introduction

Essential polyunsaturated fatty acids (PUFAs) is important bio compounds in maintaining on normal or cancer cell functions [1]. Omega-3 polyunsaturated fatty acid (n-3 PUFA) and Omega-6 polyunsaturated fatty acid (n-6 PUFA) are associated with several diseases [2]. Linoleic acid is n-6 PUFA and it can be converted to arachidonic acid. Arachidonic acid is a polyunsaturated fatty acid and it is present in the phospholipids. The arachidonic acid is metabolized by phospholipase A2 (PLA2) involved in the regulation of inflammatory [3]. n-3 PUFA is beneficial to human health. However, n-3 PUFA cannot be synthesized in human body. Foods high in omega-3 polyunsaturated fatty acid include fish, vegetable oils and nuts. The three main n-3 PUFAs are eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA). A lot of in vitro and in vivo studies have shown that n-6 PUFA induce tumorigenesis [4-6]. Much evidence has shown that n-3 PUFA may be critical to preventing cardiovascular diseases, diabetes and cancers because of antioxidation and anti-inflammatory activities. High n-6 PUFA consumption is associated with the development of cancers and diseases [2,5,7]. Therefore, the consumption of n-3 PUFAs is positive impact of preventing disease. A lot of studies have shown that high omega-3-PUFA to n-6 PUFA is a strategy to prevent diseases. The current western diet is very high in n-6 PUFA and the ratio of n-6 PUFA / n-3 PUFA has risen to up to 20-30:1, pro-inflammatory and pro-thrombotic eicosanoids generated from omega-6 fatty acids are produced in larger quantities than those derived from omega-3 fatty acids [8].

EPA and DHA are rich in fish oil. Many studies have shown that EPA or DHA enhance the immune response and induce apoptosis in cancer cells. Due to special biological properties, n-3 PUFA has minimal negative effects in normal cells. Previous studies have indicated the role of fish and marine n-3 fatty acids in cancer prevention. In this review, we will discuss the pharmacological activities of EPA and DHA in breast and colon cancer.

Colon cancer

Carcinoma of the colon or rectum (or colorectal cancer, CRC) is the second leading cause of cancer-related deaths in the United States and the third most common cancer in men and in women [9]. The risk of developing CRC is influenced by both environmental and genetic factors. Lifestyle is major risk factors that may contribute to an increased risk of colorectal cancer including lack of regular physical activity, a diet low in fruit and vegetables, a low-fiber and high-fat diet, or overweight and obesity. Other risk factors include inflammatory bowel disease such as Crohn’s disease or ulcerative colitis. Fish oil in diet may lower risk of death from CRC.

Anti-inflammatory and effects of n-3 PUFAs in colon cancer

A chronic systemic inflammatory response is clearly implicated in the progressive nutritional and functional decline in the cancer patients and their subsequent poor outcome [10]. Many chronic diseases including cardiovascular disease, diabetes, cancer, obesity, autoimmune diseases, rheumatoid arthritis, asthma and depression are associated with increased production of inflammatory mediators including thromboxane A2 (TXA2), leukotriene B4 (LTB4), IL-1, IL-6, tumor necrosis factor (TNF), and c-reactive protein [4,11,12]. Studies have shown that cancer development is associated with over expression of cyclooxygenase (COX) and lipoxygenase (LOX) [13]. n-3 PUFAs seem to act as anti-tumor promoters in CRC carcinogenesis, like non-steroidal anti-inflammatory drugs (NSAIDs).n-3 PUFAs (mainly EPA and DHA) may play competitive roles, including apoptosis, against respective properties as n-6 family pharmacologic chemicals in LOX and COX pathways [14-17]. In a population study, the serum levels of IL-6, IL-1 and TNF-a were decreased in n-3 PUFAs population. It has suggested that DHA can inhibit colon cancer growth via COX-2 dependent inhibition or COX-2 independent inhibition [9,16,18,19].

The combination therapy is considered as a strategy to enhance the chemotherapy drugs activities. The combination of n-3 PUFAs with chemopreventive phytochemicals are shown in many various experiments [20,21]. In summary, n-3 PUFAs (EPA and DHA) can enhance chemotherapeutic effects and be considered as supportive therapy. n-3 PUFAs inhibit colon cancer growth by modulating redox balance and decreasing inflammatory.

The Effects of n-3 PUFAs in breast cancer

Breast cancer is a leading cause of death in the world. Research has shown that genetic and non-genetic factors may carry an increased risk of developing breast cancer. Non-genetic factors include reproductive factors, body mass index, alcohol intake and physical activity. A number of breast cancer related genes have been identified, including BRCA 1, BRCA 2, ATM, p53, HER2 and PTEN in breast cancer cases [22,23].

Epidermal Growth Factor Receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) are receptor tyrosine kinases. EGFR over expression is associated with cancer progression in breast cancer. A study has shown that DHA can down-regulate EGFR expression and induce apoptosis in breast cancer [24]. BRCA1 and BRCA2 mutations are the cause of most hereditary breast cancer. The risk for developing breast cancer is 80% with BRCA1 mutations and 60% with BRCA2 [25]. BRCA1 and BRCA1 proteins are highly involved in ensuring genome stability. BRCA1 is involved in both the checkpoint activation and DNA repair, whereas primarily function of BRCA2 protein is in homologous recombination through its RAD51-binding activity [25,26]. The tumor suppressor p53 has been implicated in many important cellular processes, including DNA repair, cell cycle arrest, senescence, and apoptosis [27,28]. p53 gene mutations were found in 65–80% of basal or the term triple negative breast cancers [28]. The overall frequency of p53 mutation in breast cancer is approximately 20% [29]. DHA has also shown to decrease cancer cell growth by increasing BRCA1 transcriptional and protein level [30,31].

Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor family of receptor tyrosine kinases (ErbBs). HER2 is over expressed in 15–30% of breast cancer cases [32]. HER2 gene is amplified on 25–50 copies in breast cancers. The ErbBs consists of four members: ErbB1 (EGFR), ErbB2 (HER2, Neu), ErbB3 (HER3) and ErbB4 (HER4) [33]. HER2 can heterodimerise with any of the other ErbB family members and results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways. The phosphorylated HER dimers activate downstream the PI3K/AKT axis and the Raf/MAPK cascade promoting cell growth, proliferation, and survival [32,34]. HER2 over expression leads to up regulation of Bcl-2, Bcl-xL, Mcl-1, and suppresses p53-mediated apoptosis by up regulation of MDM2 and activation of AKT [35]. An in vitro study has indicated DHA inhibits HER2 activity and Akt signaling molecules leading to cell death [36].

Conclusion

EPA and DHA are rich in fish oil. A lot of studies have indicated that EPA and DHA can prevent carcinogenesis and induce cancer cell death in vivo and in vitro study through multiple mechanisms (Figure 1). EPA and DHA can change cellular and molecular level by activating or suppressing signaling pathways, transcription factors and gene expressions. Moreover, EPA and DHA might improve the efficacy of chemotherapeutic agent in many studies through suppression of inflammation or induction of apoptosis. Most studies of EPA and DHA in preventing carcinogenesis are from in vitro or in vivo. In the future, the clinical studies should be conducted.

    

    

    Figure 1:  The benefits and chemotherapeutic effect of fish oil.