tacrolimus and Carcinogenesis

Familial adenomatous polyposis (FAP) was found to be completely reversed in a patient treated with mycophenolate mofetil (MMF) and tacrolimus following kidney transplantation. In this preliminary study, we assessed whether MMF and tacrolimus alone or in combination interfere with the cell cycle and proliferation in a human colonic adenocarcinoma cell line and in the colonic polyps of the patient with FAP.. Human colonic adenocarcinoma HT-29 cells were treated with tacrolimus and MMF alone and in combination at different concentrations. Cell viability and proliferation were assessed using the MTT assay. Cell-cycle distribution was analyzed by flow cytometry. Expression of Ki-67, a marker of mitotic activity, was evaluated in the patient's colonic polyps before and under drug treatment.. MMF in combination with tacrolimus induced S-phase cell-cycle arrest and markedly inhibited HT-29 cell proliferation. Ki-67 expression in the patient's colonic polyps was significantly reduced following combined tacrolimus and MMF treatment.. MMF and tacrolimus synergistically inhibited proliferation of a human colonic adenocarcinoma cell line and interfered with the expansion of colonic crypt proliferation in the polyp from a patient with FAP. The results confirm our clinical observation and indicate the possibility of novel approach to therapy of colorectal neoplasia.

Topics: Adenocarcinoma; Adenomatous Polyposis Coli; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Cell Cycle Checkpoints; Cell Proliferation; Colon; Colonic Neoplasms; Drug Synergism; HT29 Cells; Humans; Immunosuppressive Agents; Ki-67 Antigen; Mycophenolic Acid; Tacrolimus

Inflammation contributes to colon cancer initiation. The disease along with allergy and autoimmunity has been on the rise in Western and more recently in developing countries. This shared rise may imply a shared cause. Streptomycetes are known as soil residents and produce numerous antiproliferative, anti-inflammatory/immunosuppressive compounds, e.g. rapamycin and tacrolimus. Recently, Streptomyces has been shown in gut microbiome with a lower prevalence in humans than nonhumans whose microbiomes might be more representative of past humans' in a hunter-gatherer and farming environment. It was previously suggested that Streptomyces producing antiproliferatives/immunosuppressants would be 'old friends' against allergy and autoimmunity as well as inflammatory bowel diseases. Here, it is suggested that these streptomycetes within gut microbiome have also been evolved as 'old friends' to suppress colon tumorigenesis through their numerous antiproliferatives/immunosuppressants. Subsequently, the shortage of exposure to nature in our current lifestyle has cost us the shortage of these friends and vulnerability to colon cancer. An attractive research area in the future would be whether the shortage of Streptomyces exposure can be the underlying reason for colon cancer, allergy and autoimmunity rise, and if the restoration of these 'old friends' through probiotics or more exposure to nature can prevent colon cancer.

Topics: Anti-Inflammatory Agents; Carcinogenesis; Colonic Neoplasms; Friends; Gastrointestinal Microbiome; Humans; Life Style; Microbiota; Probiotics; Sirolimus; Soil; Soil Microbiology; Streptomyces; Tacrolimus

Acute myeloid leukemia is a clonal malignant disorder derived from a small number of leukemic stem cells (LSCs). Rearrangements of the mixed lineage leukemia (MLL) gene are found in acute myeloid leukemia associated with poor prognosis. The upregulation of Hox genes is critical for LSC induction and maintenance, but is unlikely to support malignancy and the high LSC frequency observed in MLL leukemias. The present study shows that MLL fusion proteins interact with the transcription factor PU.1 to activate the transcription of CSF-1R, which is critical for LSC activity. Acute myeloid leukemia is cured by either deletion of PU.1 or ablation of cells expressing CSF-1R. Kinase inhibitors specific for CSF-1R prolong survival time. These findings indicate that PU.1-mediated upregulation of CSF-1R is a critical effector of MLL leukemogenesis.

Topics: Animals; Carcinogenesis; Gene Expression Regulation, Leukemic; Genes, Homeobox; Histone-Lysine N-Methyltransferase; Leukemia, Myeloid, Acute; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid-Lymphoid Leukemia Protein; Neoplastic Stem Cells; Phenylurea Compounds; Prognosis; Proto-Oncogene Proteins; Receptor, Macrophage Colony-Stimulating Factor; Recombinant Fusion Proteins; Signal Transduction; Tacrolimus; Thiazoles; Trans-Activators; Transcription, Genetic; Transcriptional Activation; Up-Regulation

Drug and chemically-induced immunosuppression has been implicated as a confounding factor for cancer development. Management of cancer in such situation is often a challenging task. We tested the efficacy of nordihydroguiaretic acid (NDGA) against immunosuppressant tacrolimus-induced augmentation of mouse skin tumorigenesis. It was observed that topical administration of tacrolimus significantly accelerated the tumor promotion events in dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA) promoted two-stage mouse skin carcinogenesis, which were accompanied by reduced CD4(+)/CD8(+) ratio of lymph nodes and serum IL-2 level. NDGA pre-treatment before each TPA application reduced the tumor incidence, its multiplicity and volume together with improvement in histopathological alterations and decrease in proliferating cell nuclear antigen (PCNA) labeling index (LI). However, NDGA had no significant influence on the immunosuppressive effect of tacrolimus. The present study demonstrates chemopreventive effect of NDGA in normal as well as in the condition of immunosuppression. Thus, NDGA has the potential to inhibit or delay the onset of tumor development during immunosuppressive regimen.

Topics: Animals; Anticarcinogenic Agents; Carcinogenesis; Female; Immunosuppressive Agents; Masoprocol; Mice; Skin; Skin Neoplasms; Tacrolimus