lactoferrin and Colorectal-Neoplasms

There have been a number of candidates for chemopreventive agents from synthetic drugs and natural compounds suggested to prevent colorectal cancer. However, they have shown modest efficacy in humans. The reason for this could be partly explained by the use of inappropriate models in vitro and in vivo, and the limitation of chemoprevention trials. In Japan, there are no cancer chemopreventive medicines, and few cancer chemoprevention trials to date. In contrast, an increase in the prevalence of colorectal cancer in Japan has forced us to develop more efficient chemopreventive strategies. It is now a good time to review in detail the current status and future prospects for chemoprevention of colorectal cancer with respect to the future development of chemopreventive medicines, particularly using synthetic drugs and natural compounds in Asian populations. The role and mode of action of available synthetic drugs, mainly aspirin and metformin, are reviewed. In addition, the possible impact of natural compounds with anti-inflammatory/immunosuppressive properties, such as ω3 polyunsaturated fatty acid and lactoferrin, are also reviewed.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Agents; Aspirin; Clinical Trials as Topic; Colorectal Neoplasms; Disease Models, Animal; Evidence-Based Medicine; Fatty Acids, Omega-3; Humans; Hypoglycemic Agents; Japan; Lactoferrin; Metformin; Molecular Targeted Therapy; Prevalence; Primary Prevention; Randomized Controlled Trials as Topic

Most abdominal disorders present with a limited number of overlapping symptoms. Blood tests are not routinely available for use in diagnosis and so investigation tends to require complex imaging procedures or endoscopy and biopsy. These are invasive for the patient, may be associated with morbidity and mortality and have considerable resource implications. Biochemical tests on a single sample of faeces are therefore a valuable alternative. Measurement of faecal calprotectin has been shown to have a role in the diagnosis of inflammatory bowel disease and in its monitoring. Lactoferrin is also of benefit used in this way. Faecal elastase has been demonstrated to be of use in the diagnosis of pancreatic insufficiency. A number of faecal markers have been explored in colorectal cancer. Faecal occult blood testing is used for population screening, but the metabolomic marker tumour, M2-pyruvate kinase, has potential for use in both diagnosis and screening. DNA testing has advantages in colorectal cancer but the exact applications of such tests require further evaluation.

Topics: Biomarkers; Carcinoma; Colorectal Neoplasms; Enzyme-Linked Immunosorbent Assay; Exocrine Pancreatic Insufficiency; Feces; Humans; Inflammatory Bowel Diseases; Lactoferrin; Leukocyte L1 Antigen Complex; Mass Screening; Metabolome; Occult Blood; Pancreatic Elastase; Pancreatitis; Pyruvate Kinase; Sensitivity and Specificity

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and, despite improved colonoscopic screening, CRC is a leading cause of death from cancer. Administration of bovine lactoferrin (bLF) suppresses carcinogenesis in the colon and other organs of test animals, and recently it was shown that ingestion of bLF inhibits the growth of adenomatous polyps in human patients. Here we review work which established bLF as an anti-carcinogenic agent in laboratory animals and the results of a clinical trial which demonstrated that bLF can reduce the risk of colon carcinogenesis in humans.

Topics: Animals; Anticarcinogenic Agents; Cattle; Colorectal Neoplasms; Humans; Lactoferrin

Topics: Biomarkers, Tumor; CD55 Antigens; Colorectal Neoplasms; Feces; Female; Hemoglobins; Humans; Lactoferrin; Male; Occult Blood; Polymorphism, Restriction Fragment Length; Positron-Emission Tomography; Sentinel Surveillance; Tomography, Spiral Computed

Lactoferrin (LF), a secreted, iron binding glycoprotein originally discovered as a component of milk, is found in a variety of exocrine secretions and in the secondary granules of polymorphonuclear leukocytes. Animal experiments have shown that oral administration of bovine lactoferrin (bLF) exerts anticarcinogenesis effects in the colon and other organs of the rat. The aim of this study was to determine whether oral bLF could inhibit the growth of adenomatous colorectal polyps in human patients. A randomized, double-blind, controlled trial was conducted in 104 participants, ages 40 to 75 years, with polyps

Topics: Adenomatous Polyps; Administration, Oral; Adult; Aged; Animals; Cattle; Colonoscopy; Colorectal Neoplasms; Female; Humans; Lactoferrin; Male; Middle Aged; Neoplasm Staging; Placebos; Prognosis; Survival Rate; Treatment Outcome

To evaluate prospectively usefulness of fecal lactoferrin (Lf) and fecal hemoglobin (Hb) in the diagnosis of colorectal diseases.. Fecal Lf and Hb were measured using ELISA in 872 patients before they underwent colorectal endoscopy.. Lf was positive in 18 (50%) of 36 patients with colorectal cancer, 25 (15.9%) of 157 with colorectal polyps, 29 (46.8%) of 62 with ulcerative colitis, and 25 (62.5%) of 40 (62.5%) with Crohn's disease. The Hb-positive rates were 50%, 12.1%, 41.9% and 32.5%, respectively. Of the 318 patients free of abnormalities by colorectal endoscopy, Lf was positive in 29 (9.1%) and Hb was positive in 15 (4.7%). Among patients with Crohn's disease, the Lf-positive rate was significantly higher than the Hb-positive rate. If either high Lf or Hb levels were considered positive, the positive rates rose to 61.1%, 51.6%, and 67.5% in the colorectal cancer group, ulcerative colitis group, and Crohn's disease group, respectively. If both high Lf and Hb levels were rated positive, the positive predictive values (PPV) were 21% for colorectal cancer, 33% for ulcerative colitis, and 17% for Crohn's disease, and PPV of high Hb level alone was 18%, 25% and 13%, respectively.. Fecal Lf and Hb were found useful in the detection of colorectal diseases, and the combination of the two measurements appears to increase the sensitivity and efficacy of diagnosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Child; Colonic Diseases; Colorectal Neoplasms; Endoscopy, Gastrointestinal; Feces; Hemoglobins; Humans; Lactoferrin; Middle Aged; Predictive Value of Tests; Prospective Studies; Rectal Diseases; Sensitivity and Specificity

Colorectal cancer (CRC) therapy is a big challenge, and seeking an effective and safe drug is a pressing clinical need. Gambogic acid is a potent antineoplastic agent without the drawback of bone marrow suppression. To improve its druggability (e.g., poor water solubility and tumor delivery), a lactoferrin-modified gambogic acid liposomal delivery system (LF-lipo) was developed to enhance the treatment efficacy of CRC. The LF-lipo can specifically bind LRP-1 expressed on colorectal cancer cells to enhance drug delivery to the tumor cells and yield enhanced therapeutic efficacy. The LF-lipo promoted tumor cell apoptosis and autophagy, reduced reactive oxygen species (ROS) levels in tumor cells, and inhibited angiogenesis; moreover, it could also repolarize tumor-associated macrophages from the M2 to M1 phenotype and induce ICD to activate T cells, exhibiting the capability of remodeling the tumor immune microenvironment. The liposomal formulation yielded an efficient and safe treatment outcome and has potential for clinical translation.

Topics: Cell Line, Tumor; Colorectal Neoplasms; Humans; Lactoferrin; Liposomes; Tumor Microenvironment

Lactoferrin (Lf) is an iron-binding glycoprotein that is present at high concentrations in milk. Bovine lactoferricin (LfcinB) is a peptide fragment generated by pepsin proteolysis of bovine lactoferrin (bLf). LfcinB consists of amino acid residues 17-41 proximal to the N-terminus of bLf and a disulfide bond between residues 19 and 36, forming a loop. Both bLf and LfcinB have been demonstrated to have antitumor activities. Colorectal cancer is the second most common cause of cancer death in developed countries. We hypothesized that bLf and LfcinB exert antitumor activities on colon cancer cells (HT-29) by triggering various signaling pathways. bLf and LfcinB significantly induced apoptosis in HT-29 cells but not in normal human intestinal epithelial cells, as revealed by the ApoTox-Glo Triplex Assay. The LIVE/DEAD cell viability assay showed that both bLf and LfcinB reduced the viability of HT-29 cells. Transcriptome analysis indicated that bLf, cyclic LfcinB, and linear LfcinB exerted antitumor activities by differentially activating diverse signaling pathways, including p53, apoptosis, and angiopoietin signaling. Immunoblotting results confirmed that both bLf and LfcinBs increased expression of caspase-8, p53, and p21, critical proteins in tumor suppression. These results provide valuable information regarding bLf and LfcinB for potential clinical applications in colon cancer therapy.

Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Apoptosis; Blotting, Western; Cattle; Cell Survival; Colorectal Neoplasms; Gene Expression Profiling; Humans; Lactoferrin; Peptide Fragments; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured

Lactoferrin (Lf), the main iron-binding protein of milk, has biological activities. We have evaluated the potential of camel milk lactoferrin for its ability to inhibit the proliferation of the colon cancer cell line, HCT-116, in vitro, DNA damage and its antioxidant activities for the first time. The antioxidant capacity of Lf was evaluated by different assays, including ferric-reducing/antioxidant power assay (FRAP), free radical-scavenging activity (DPPH), nitric oxide (NO) radical-scavenging assay, total antioxidant activity and DNA damage, compared with vitamin C and rutin.

Topics: Animals; Antioxidants; Camelus; Cell Proliferation; Colorectal Neoplasms; DNA Damage; Down-Regulation; HCT116 Cells; Humans; Lactoferrin; Milk

Colorectal cancer is a significant source of morbidity and mortality in the United States and other Western countries. Oral delivery of therapeutics remains the most patient accepted form of medication. The development of an oral delivery formulation for local delivery of chemotherapeutics in the gastrointestinal tract can potentially alleviate the adverse side effects including systemic cytotoxicity, as well as focus therapy to the lesions. Here we develop an oral formulation of the chemotherapeutic drug oxaliplatin for the treatment of colorectal cancer. Oxaliplatin was encapsulated in pH sensitive, mucoadhesive chitosan-coated alginate microspheres. The microparticles were formulated to release the chemotherapeutics after passing through the acidic gastric environment thus targeting the intestinal tract. In vivo, these particles substantially reduced the tumor burden in an orthotopic mouse model of colorectal cancer, and reduced mortality.

Topics: Administration, Oral; Animals; Body Weight; C-Reactive Protein; Colorectal Neoplasms; Drug Compounding; Immunohistochemistry; Lactoferrin; Male; Mice; Mice, Inbred C57BL; Organoplatinum Compounds; Oxaliplatin

We have established a medium-term colorectal carcinogenesis rat model initiated with 1,2-dimethylhydrazine (DMH) followed by dextran sodium sulfate (DSS) treatment, featuring induction of neoplastic lesions within 10 weeks. In the present study, we examined its ability to detect modification of colon lesion development with 10- or 20-week experimental periods. F344 male rats were given three subcutaneous injections of DMH (40 mg/kg b.w.) in a week followed by free access to drinking water containing 1% DSS for a week. One week after this regimen, basal diet alone, basal diet containing 0.04% nimesulide or 2% lactoferrin as known inhibitors, 0.3% deoxycholic acid (DCA) as a promoter or 1.5% 1-hydroxyanthraquinone (1-HA) as a carcinogen were supplied. At week 10, the incidence and multiplicity of combined adenomas and adenocarcinomas were significantly (P < 0.05 or 0.01) decreased by nimesulide and lactoferrin, and values for adenomas were significantly (P < 0.01) increased in the 1-HA group. There was no clear change in the DCA group. At week 20, multiplicity and volume of the tumors were significantly (P < 0.01 or 0.05) decreased by nimesulide, but no effect was now evident with lactoferrin. Multiplicity and volume of tumors were significantly (P < 0.01) increased in 1-HA group and a similar tendency was apparent (P = 0.08) with DCA. It is concluded that this system offers a useful tool for detection of colorectal carcinogenesis modifiers within 10-20 weeks, pending further studies for verification employing other model chemicals.

Topics: 1,2-Dimethylhydrazine; Animals; Anthraquinones; Carcinogenicity Tests; Colorectal Neoplasms; Deoxycholic Acid; Dextran Sulfate; Lactoferrin; Male; Precancerous Conditions; Rats; Rats, Inbred F344

Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity.. Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration.. Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion.. These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

Topics: Aged; Angiogenesis Inhibitors; Antigens, CD; Biomarkers, Tumor; CD24 Antigen; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Indoles; Lactoferrin; Leukocytes, Mononuclear; Male; Matrix Metalloproteinase 9; Membrane Glycoproteins; Middle Aged; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Predictive Value of Tests; Protein-Tyrosine Kinases; Pyrroles; Reverse Transcriptase Polymerase Chain Reaction