icg-001 and Colorectal-Neoplasms

Wnt/β-catenin pathway is one of the main/frequent dysregulated pathways in several tumor types, including colon cancer. Aberrant activation of this pathway is associated with cell proliferation, invasive behaviors, and cell resistance, suggesting its potential value as a therapeutic target in treatment of CRC. Several agents have been developed for targeting of this pathway (e.g, natural agents: curcumin, 3,3-diindolylmethane, phytoestrogen; Synthetic/small Wnt inhibitors: Rofecoxib; PRI-724, CWP232291; and monoclonal antibody against frizzled receptors, Vanituctumab). This review summarizes the current knowledge about the therapeutic potential of targeting Wnt pathway with particular emphasis on preclinical/clinical studies in treatment of colorectal cancer. J. Cell. Biochem. 118: 1979-1983, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Animals; Antineoplastic Agents; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Indoles; Lactones; Molecular Targeted Therapy; Pyrimidinones; Signal Transduction; Sulfones; Wnt Proteins

Recurrence and metastasis remain major obstacles in colorectal cancer (CRC) treatment. Recent studies suggest that a small subpopulation of cells with a self-renewal ability, called cancer stem-like cells (CSCs), promotes recurrence and metastasis in CRC. Unfortunately, no CSC inhibitor has been demonstrated to be more effective than existing chemotherapeutic drugs, resulting in a significant unmet need for effective CRC therapies. In this study, transcriptomic profiling of metastatic tumors from CRC patients revealed significant upregulation in the Wnt pathway and stemness genes. Thus, we examined the therapeutic effect of the small-molecule Wnt inhibitor ICG-001 on cancer stemness and metastasis. The ICG-001 treatment efficiently attenuated self-renewal activity and metastatic potential. Mechanistically, myeloid ecotropic viral insertion site 1 (MEIS1) was identified as a target gene of ICG-001 that is transcriptionally regulated by Wnt signaling. A series of functional analyses revealed that MEIS1 enhanced the CSC behavior and metastatic potential of the CRC cells. Collectively, our findings suggest that ICG-001 efficiently inhibits CRC stemness and metastasis by suppressing MEIS1 expression. These results provide a basis for the further clinical investigation of ICG-001 as a targeted therapy for CSCs, opening a new avenue for the development of novel Wnt inhibitors for the treatment of CRC metastasis.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Colorectal Neoplasms; Gene Expression Profiling; HCT116 Cells; HT29 Cells; Humans; Male; Mice; Mice, Inbred NOD; Myeloid Ecotropic Viral Integration Site 1 Protein; Neoplastic Stem Cells; Pyrimidinones; Small Molecule Libraries; Transcription, Genetic; Wnt Signaling Pathway

Most solid tumors contain a subfraction of cells with stem/progenitor cell features. Stem cells are naturally chemoresistant suggesting that chronic chemotherapeutic stress may select for cells with increased "stemness". We carried out a comprehensive molecular and functional analysis of six independently selected colorectal cancer (CRC) cell lines with acquired resistance to three different chemotherapeutic agents derived from two distinct parental cell lines. Chronic drug exposure resulted in complex alterations of stem cell markers that could be classified into three categories: 1) one cell line, HT-29/5-FU, showed increased "stemness" and WNT-signaling, 2) three cell lines showed decreased expression of stem cell markers, decreased aldehyde dehydrogenase activity, attenuated WNT-signaling and lost the capacity to form colonospheres and 3) two cell lines displayed prominent expression of ABC transporters with a heterogeneous response for stem cell markers. While WNT-signaling could be attenuated in the HT-29/5-FU cells by the WNT-signaling inhibitors ICG-001 and PKF-118, this was not accompanied by any selective growth inhibitory effect suggesting that the cytotoxic activity of these compounds is not directly linked to WNT-signaling inhibition. We conclude that classical WNT-signaling inhibitors have toxic off-target activities that need to be addressed for clinical development.

Topics: Antineoplastic Agents; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; Camptothecin; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Hyaluronan Receptors; Irinotecan; Neoplastic Stem Cells; Organoplatinum Compounds; Oxaliplatin; Protein Isoforms; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; Triazines; Wnt Signaling Pathway

A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described. These compounds were used as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt/TCF4/β-catenin-driven transcription or viability. The findings suggest that the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function, such as its putative role in stabilizing the TCF4/β-catenin transcriptional complex.

Topics: Aminopyridines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Drug Discovery; Enzyme Activation; Humans; Inhibitory Concentration 50; Models, Molecular; Molecular Structure; Protein Serine-Threonine Kinases; Signal Transduction