Mechanistic insights into anticancer properties of oligomeric proanthocyanidins from grape seeds in colorectal cancer.

Although the anticancer properties of oligomeric proanthocyanidins (OPCs) from grape seeds have been well recognized, the molecular mechanisms by which they exert anticancer effects are poorly understood. In this study, through comprehensive RNA-sequencing-based gene expression profiling in multiple colorectal cancer cell lines, we for the first time illuminate the genome-wide effects of OPCs from grape seeds in colorectal cancer. Our data revealed that OPCs affect several key cancer-associated genes. In particular, genes involved in cell cycle and DNA replication were most significantly and consistently altered by OPCs across multiple cell lines. Intriguingly, our in vivo experiments showed that OPCs were significantly more potent at decreasing xenograft tumor growth compared with the unfractionated grape seed extract (GSE) that includes the larger polymers of proanthocyanidins. These findings were further confirmed in colorectal cancer patient-derived organoids, wherein OPCs more potently inhibited the formation of organoids compared with GSE. Furthermore, we validated alteration of cell cycle and DNA replication-associated genes in cancer cell lines, mice xenografts as well as patient-derived organoids. Overall, this study provides an unbiased and comprehensive look at the mechanisms by which OPCs exert anticancer properties in colorectal cancer.

Essential turmeric oils enhance anti-inflammatory efficacy of curcumin in dextran sulfate sodium-induced colitis.

Turmeric has been used as a medicinal herb for thousands of years for treatment of various disorders. Although curcumin is the most studied active constituents of turmeric, accumulating evidence suggests that other components of turmeric have additional anti-inflammatory and anti-tumorigenic properties. Herein, we investigated anti-inflammatory efficacy and associated gene expression alterations of a specific, curcumin preparation containing essential turmeric oils (ETO-curcumin) in comparison to standard curcumin at three specific doses (0, 5, 25 or 50 mg/kg), in an animal model of dextran sodium sulfate (DSS)-induced colitis. The present study showed that both ETO and standard curcumin treatments provided protection against DSS-induced inflammation. However, ETO-curcumin improved disease activity index (DAI) dose-dependently, while the anti-inflammatory efficacy of standard curcumin remained constant, suggesting that ETO-curcumin may provide superior anti-inflammatory efficacy compared to standard curcumin. Gene expression analysis revealed that anti-inflammatory cytokines including IL-10 and IL-11 as well as FOXP3 were upregulated in the colon by ETO-curcumin. Collectively, these findings suggest that the combined treatment of curcumin and essential turmeric oils provides superior protection from DSS-induced colitis than curcumin alone, highlighting the anti-inflammatory potential of turmeric.

The Holy Grail of Curcumin and its Efficacy in Various Diseases: Is Bioavailability Truly a Big Concern?

The powdered rhizome of turmeric has been extensively used in India and other South Asian cuisines, and is an integral part of Ayurvedic medicine for a broad range of conditions. In particular, curcumin, a major active component of turmeric, is one of the most studied botanicals for its anti-inflammatory, anti-oxidant and anti-cancer properties. Despite its well-documented therapeutic efficacy, for years the limited systemic bioavailability of curcumin has hindered its development as a potential therapeutic agent. However, recent introduction of unique extraction processes and various delivery methods has resulted in the development of new curcumin formulations and significantly improved its bioavailability. While these new formulations will no doubt expand curcumin's therapeutic potential, there are notable inconsistencies surrounding curcumin's bioavailability and corresponding bioactivity, raising some important questions. This article dissects various contributing factors of curcumin bioavailability to identify possible causes for the discrepancies associated with its bioactivity and discuss how these new curcumin formulations could further improve its clinical usefulness.

Novel Evidence for Curcumin and Boswellic Acid-Induced Chemoprevention through Regulation of miR-34a and miR-27a in Colorectal Cancer.

Colorectal cancer is one of the most common causes of cancer-associated mortality worldwide, but it is truly a preventable disease. Both curcumin and boswellic acids are well-established dietary botanicals with potent antitumorigenic properties that have been shown to modulate multiple oncogenic pathways. Recent data suggest that the chemopreventive effects of these botanicals may, in part, be mediated through regulation of key cancer-related microRNAs (miRNA) and their downstream gene targets. Here, we investigated the antitumorigenic effects of curcumin and 3 acetyl-11-keto-ß-boswellic acid (AKBA) on modulation of specific cancer-related miRNAs in colorectal cancer cells and validated their protective effects in vivo using a xenograft mouse model. Both curcumin and AKBA inhibited cellular proliferation, induced apoptosis and cell-cycle arrest in colorectal cancer cell lines, and these effects were significantly enhanced with combined treatment. Gene-expression arrays revealed that curcumin and AKBA regulated distinct cancer signaling pathways, including key cell-cycle regulatory genes. Combined bioinformatics and in silico analysis identified apoptosis, proliferation, and cell-cycle regulatory signaling pathways as key modulators of curcumin and AKBA-induced anticancer effects. We discovered that curcumin and AKBA induced upregulation of tumor-suppressive miR-34a and downregulation of miR-27a in colorectal cancer cells. Furthermore, we demonstrated in a mouse xenograft model that both curcumin and AKBA treatments suppressed tumor growth, which corresponded with alterations in the expression of miR-34a and miR-27a, consistent with our in vitro findings. Herein, we provide novel mechanistic evidence for the chemopreventive effects of curcumin and AKBA through regulation of specific miRNAs in colorectal cancer.

The importance of diets and epigenetics in cancer prevention: a hope and promise for the future?

Although it is impossible to fathom innumerable differences in environmental, lifestyle, and socioeconomic differences in populations globally, one element that unequivocally stands out is the striking "dietary" differences between these regions versus those in developed countries, where the staple diet is primarily based on some variation of a conventional Western diet. It is hard to dismiss the overwhelming body of large-scale epidemiological data, adjusted for key variables, which clearly highlights that dietary differences alone can help account for some of the disease disparity witnessed worldwide. The classic view of cancer initiation is that cancer results from alterations in our genome, which closely associates with the dynamics of gene expression that occurs between oncogenes (cancer-promoting genes) and tumor suppressor genes (cancer-inhibitory genes). Interestingly, scientific research for the last few decades has now clearly revealed that alterations in the expression of these genes is rarely manifested by the "genetic" events themselves, and that only approximately 2% to 5% of the majority of cancers, particularly colorectal cancers, are driven by germline mutations (which can be hereditarily passed onto subsequent generations) in cancer-related genes. In only the last decade, we have recognized that expression of cancer-associated genes in the majority of sporadic cancers is actually controlled by a unique process, defined as epigenetics-a process that can influence gene expression, without causing a permanent alteration in a gene (or DNA). Such epigenetic alterations can occur in a heritable manner, are not permanent (hence reversible), and can be easily modified by dietary and environmental stimuli. Epigenetics helps us understand that genetic or hereditary forms of most cancers are extremely rare and that most cancers can be realistically prevented or managed by making simple day-to-day changes in our diets.

Dose-dependent reduction of dietary protein-induced colonocyte DNA damage by resistant starch in rats correlates more highly with caecal butyrate than with other short chain fatty acids.

Previous studies have shown increased levels of colonocyte DNA damage (as measured by the comet assay) and thinning of the colonic mucus layer in rats fed higher dietary protein as casein or red meat with highly digestible starch. Feeding resistant starch (RS) as high amylose maize starch (HAMS) opposed these changes. However, the dietary level of HAMS was relatively high (48% by weight) so this study was conducted to establish whether HAMS had the same effects at lower dietary levels. Adult male rats were fed a diet containing 25% casein with 0%, 10%, 20%, 30% or 40% HAMS for 4 wk. DNA single strand breaks and 8-hydroxyguanosine levels were measured in isolated colonocytes by the comet assay. As expected, comet tail moment was greatest and the mucus barrier thinnest in rats fed 0% HAMS. DNA damage was reduced and the mucus barrier thickened in a logarithmic dose-dependent manner by HAMS. There was no significant difference in 8-hydroxyguanosine between dietary groups. Caecal and fecal short chain fatty acid (SCFA) pools rose with the increased level of dietary HAMS. DNA damage of colonocytes correlated negatively with caecal SCFA but the strongest correlation was with caecal butyrate, which is consistent with the proposed role of this SCFA in promoting a normal cell phenotype. These data show that HAMS prevents protein-induced colonic DNA damage in a dose-dependent manner. Inclusion of 10% HAMS was found to be sufficient to oppose colonocyte DNA damage, and to increase caecal and fecal SCFA pools.