Abstract:Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer.
The general population is encouraged to increase omega-3 polyunsaturated fatty acid (n-3 PUFA) intake in order to optimize health for preventative health care. Consumers are typically unaware that different amounts, types, and structural forms of n-3 PUFA have different efficacy. Therefore, the objectives of this study were to characterize different sources of n-3 PUFAs and to determine whether consumption of these oils influences renal fatty acid composition and renal health. Lipid classes and fatty acid profile of corn (CO), flaxseed (FO), menhaden (MO), salmon (SO), tuna (TO) or krill (KO) oils were determined by thin-layer and gas chromatography. All dietary oils consisted of >65% triglyceride with the exception of KO. KO and FO also contained phospholipids. FO was rich in the n-3 PUFA, alpha-linolenic acid (18:3n-3) whereas, the marine oils were rich in the long-chain n-3 PUFAs (>18 carbons). Following characterization of the oil sources, female Sprague-Dawley rats (age 28 d) were randomly assigned (n = 10/group) to be fed a high fat 12% (wt) diet consisting of these different oil sources for 8 weeks. Rats fed MO, TO, and SO had significantly higher renal eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3) deposition and this in turn, modulated inflammatory responses. Feeding rats MO, SO and TO reduced urinary excretion of 13,14-dihydro-15-keto prostaglandin E2. Feeding rats TO and SO reduced (P ≤ 0.002) nuclear factor kappa B activity and circulating TNFα (P < 0.05). In contrast, rats consuming KO had heavier kidney weights (P < 0.001), total calcium content, and histological evidence of renal calcification and tubulo-interstitial injury. This was due to increased (P < 0.001) urinary phosphorus excretion associated with the phospholipids content of KO. The study results indicated that consumption of n-3 PUFAs influences renal health and the effects varied depending on the n-3 PUFA source consumed.
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