Curcumin Chemosensitizes 5-Fluorouracil Resistant MMR-Deficient Human Colon Cancer Cells in High Density Cultures

Objective Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50–60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells. Methods High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays. Results Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting. Conclusion Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population

Implications of Biosecurity in Food Safety

Owing to growing population of world, efforts are being made to maximise food production. Food safety should not be compromised to meet the food requirement of increasing population. Biosecurity is the imperative approach to ensure food safety. This is a holistic approach that interlinks health, environment, security and trade. Increased incidents of foodborne diseases led to promotion of biosecurity as a major priority policy worldwide to curtail such incidents and ensure food safety. Microbial risk management is an essential component of food safety. National biosecurity programmes are essentially required to identify the prospective modes of introduction and spread of a disease in a country or region and to specify the control measures to curtail the risk associated with the disease. International standards for various biosecurity sectors are set mainly by Codex Alimentarius Commission, the World Organisation for Animal Health and Commission on Phytosanitary Measures, which are implemented through the Sanitary and Phytosanitary Agreement, 1995 of World Trade Organisation. Agricultural biosecurity is of utmost importance in the countries that are large crop and animal producers, and these countries are at risk from alien pests and pathogens. Adequate biosecurity programmes are essential in all the countries to protect global environment, agriculture and biodiversity. Developing countries, particularly with large populations aiming maximised food production require stringent biosecurity approaches to provide safe and nutritious food to the people

Detection of Fecal DNA Methylation for Colorectal Neoplasia : Does It Lead to an Optimal Screening Test?

Aberrant promoter methylation, an 'epigenetic' form of genomic instability that leads to transcriptional silencing of tumor suppressor genes, is increasingly being recognized as a crucial component in the evolution of human cancers. With our limited knowledge of the molecular basis and timing of the initiation of altered methylation events in the stepwise progression of cancers, the biggest challenge we currently face is to identify novel biomarkers and technologies for the timely screening of patients carrying such alterations. One such strategy would be to develop tests for the detection of fecal DNA methylation patterns that will improve the sensitivity of noninvasive screening tests for colorectal neoplasia, and moreover, will decrease both mortality and the incremental costs of treating colorectal cancers

LAMC2 promotes gemcitabine resistance in PDAC

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis. Gemcitabine remains an effective option for the majority of PDAC patients. Unfortunately, currently no reliable prognostic and predictive biomarkers of therapeutic response are available for the patients with PDAC. Laminin γ2 (LAMC2) is overexpressed in several cancers, and its high expression facilitates cancer development and chemoresistance. However, its functional role in PDAC remains unclear, and a better understanding of this will likely help improve the prognosis of PDAC patients. This study aimed to elucidate the clinical and biological role of LAMC2 in PDAC. We first analyzed the expression levels of LAMC2 by real-time reverse transcription PCR in a cohort of 114 PDAC patients. Interestingly, higher expression of LAMC2 significantly correlated with poor survival in PDAC cohort. In addition, elevated LAMC2 expression served as a potential prognostic marker for survival. Subsequently, functional characterization for the role of LAMC2 in PDAC was performed by small interfering RNA (siRNA) knockdown in pancreatic cancer (PC) cell lines. Interestingly, inhibition of LAMC2 in PC cells enhanced the gemcitabine sensitivity and induction of apoptosis. Moreover, it inhibited colony formation ability, migration, and invasion potential. Furthermore, LAMC2 regulated the expression of epithelial-mesenchymal transition (EMT) phenotype. In addition, LAMC2 significantly correlated with genes associated with the expression of ATP-binding cassette (ABC) transporters in PC cells and PDAC patients. In conclusion, these results suggest that LAMC2 regulates gemcitabine sensitivity through EMT and ABC transporters in PDAC and may be a novel therapeutic target in PDAC patients

Probiotics: Microbial Therapy for Health Modulation

The human gastrointestinal tract is a complex ecosystem that harbours a rich and diversemicroflora. These microbes live in harmony with the host and exert various beneficial effects onhuman health by their metabolic activities. However, in our modern life style, frequent andindiscriminate use of antibiotics has disturbed this microbial ecosystem, resulting in occurrenceof various bowel diseases. Some live microbial food supplements can re-establish this microbialecosystem. Such a group of microorganisms, which positively influences the intestinal microbiotaby stimulating the growth of beneficial bacteria and suppressing the harmful ones, is collectivelyknown as probiotics. These have been consumed in the form of fermented milk products forcenturies. However, scientific interest in their use for health maintenance and disease preventionhas emerged over the past few years only.Various scientific evidences show that probiotics help to reduce several disorders includingdiarrhea, inflammatory bowel diseases, urinary tract infections, hypertension, allergies, and cancer.Besides, probiotics exert several other benefits also to human beings and animals. Importantissues in the probiotic therapy include selection of appropriate strain, its viability during storage,gut persistence potential and functional properties. Another category involved in gut health isprebiotics. These are non-digestible food ingredients, which beneficially affect the host byselectively stimulating the growth or activity of one or a limited number of beneficial bacteriain the colon. This review paper highlights the major health benefits of probiotic organisms,mechanisms of their action, criteria of selection, enumeration, and safety of their use for humanhealth

Sirt1 Is Required for Resveratrol-Mediated Chemopreventive Effects in Colorectal Cancer Cells

Sirt1 is a NAD(+)-dependent protein-modifying enzyme involved in regulating gene expression, DNA damage repair, metabolism and survival, as well as acts as an important subcellular target of resveratrol. The complex mechanisms underlying Sirt1 signaling during carcinogenesis remain controversial, as it can serve both as a tumor promoter and suppressor. Whether resveratrol-mediated chemopreventive effects are mediated via Sirt1 in CRC growth and metastasis remains unclear;which was the subject of this study. We found that resveratrol suppressed proliferation and invasion of two different human CRC cells in a dose-dependent manner, and interestingly, this was accompanied with a significant decrease in Ki-67 expression. By transient transfection of CRC cells with Sirt1-ASO, we demonstrated that the anti-tumor effects of resveratrol on cells was abolished, suggesting the essential role of this enzyme in the resveratrol signaling pathway. Moreover, resveratrol downregulated nuclear localization of NF-kappa B, NF-kappa B phosphorylation and its acetylation, causing attenuation of NF-kappa B-regulated gene products (MMP-9, CXCR4) involved in tumor-invasion and metastasis. Finally, Sirt1 was found to interact directly with NF-kappa B, and resveratrol did not suppress Sirt1-ASO-induced NF-kappa B phosphorylation, acetylation and NF-kappa B-regulated gene products. Overall, our results demonstrate that resveratrol can suppress tumorigenesis, at least in part by targeting Sirt1 and suppression of NF-kappa B activation