monensin and Colorectal-Neoplasms

Colorectal cancer is the third leading cause of death in patients with cancers in America. Monensin has represented anti-cancer effect on various human cancer cells. We seek to investigate the effect of monensin on proliferation of human colorectal cancer cells and explore whether IGF1R signaling pathway is involved in anti-cancer mechanism of monensin.. Cell proliferation and migration were assessed by crystal violet staining and cell wounding assay respectively. Cell apoptosis was analyzed by Hoechst 33258 staining and flow cytometry. Cell cycle progression was detected with the use of flow cytometry. Cancer-associated pathways were assessed with the use of pathway-specific reporters. Gene expression was detected by touchdown-quantitative real-time PCR. Inhibition of IGF1R was tested by immunofluorescence staining. Inhibition of IGF1R signaling was accomplished by adenovirus-mediated expression of IGF1.. We found that monensin not only effectively inhibited cell proliferation, cell migration as well as cell cycle progression, but also induced apoptosis and G1 arrest in human colorectal cancer cells. Monensin was shown to target multiple cancer-related signaling pathways such as Elk1, AP1, as well as Myc/max, and suppressed IGF1R expression. Monensin could suppressed IGF1R expression

Topics: Anti-Bacterial Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Humans; Monensin; Neoplasms; Receptor, IGF Type 1; Signal Transduction

Topics: Anti-Bacterial Agents; Colorectal Neoplasms; Humans; Interferon Regulatory Factor-3; Monensin; RNA, Messenger; Signal Transduction; Toll-Like Receptor 4

The Wnt signaling pathway is required during embryonic development and for the maintenance of homeostasis in adult tissues. However, aberrant activation of the pathway is implicated in a number of human disorders, including cancer of the gastrointestinal tract, breast, liver, melanoma, and hematologic malignancies. In this study, we identified monensin, a polyether ionophore antibiotic, as a potent inhibitor of Wnt signaling. The inhibitory effect of monensin on the Wnt/β-catenin signaling cascade was observed in mammalian cells stimulated with Wnt ligands, glycogen synthase kinase-3 inhibitors, and in cells transfected with β-catenin expression constructs. Furthermore, monensin suppressed the Wnt-dependent tail fin regeneration in zebrafish and Wnt- or β-catenin-induced formation of secondary body axis in Xenopus embryos. In Wnt3a-activated HEK293 cells, monensin blocked the phoshorylation of Wnt coreceptor low-density lipoprotein receptor related protein 6 and promoted its degradation. In human colorectal carcinoma cells displaying deregulated Wnt signaling, monensin reduced the intracellular levels of β-catenin. The reduction attenuated the expression of Wnt signaling target genes such as cyclin D1 and SP5 and decreased the cell proliferation rate. In multiple intestinal neoplasia (Min) mice, daily administration of monensin suppressed progression of the intestinal tumors without any sign of toxicity on normal mucosa. Our data suggest monensin as a prospective anticancer drug for therapy of neoplasia with deregulated Wnt signaling.

Topics: Animals; Antibiotics, Antineoplastic; beta Catenin; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Low Density Lipoprotein Receptor-Related Protein-6; Mice; Monensin; Neoplasms, Experimental; Wnt Signaling Pathway; Xenograft Model Antitumor Assays; Xenopus; Zebrafish

The carboxylic ionophore monensin could be successfully entrapped in small unilamellar vesicles made by the extruder method. Monensin liposomes of size range 100-150 nm were more potent in potentiating ricin A immunotoxin activity in vitro as compared to monensin liposomes of diameter 500 nm or more. These liposomes were further successfully linked to tumor specific monoclonal antibodies with full retention of immunoreactivity. Monoclonal antibody targeted monensin liposomes were 100 times more potent than monensin liposomes in potentiating the activity of ricin A immunotoxins against various tumor cell lines in vitro.

Topics: Antibodies, Monoclonal; Colorectal Neoplasms; Drug Stability; Drug Synergism; Humans; Immunotoxins; Liposomes; Monensin; Ricin; Tumor Cells, Cultured

The utilization of carboxylic ionophores such as monensin for immunotoxin potentiation may be hampered by the poor solubility and short in vivo half-life of these highly lipophilic compounds. Therefore, the use of monensin formulated in a lipid/water emulsion was investigated for the in vitro and in vivo potentiation of immunotoxins. Monensin in emulsion or in buffer was equally effective for the in vitro potentiation of the cytotoxicity of both anti-human transferrin receptor and anti-carcinoembryonic antigen immunotoxins against target cells. In mice, buffer and lipid emulsion were compared as vehicles for the i.p. administration of monensin. The half-life of monensin in the peritoneal cavity of BALB/c x DBA/2 F1 (CD2F1) mice was increased 20-fold by inclusion in lipid emulsion (13 min versus 0.75 min). Treatment i.p. with anti-human transferrin receptor immunotoxin or anti-carcinoembryonic antigen immunotoxin and monensin emulsion prolonged the survival of mice with macroscopic i.p. tumor xenografts of H-Meso-1 mesothelioma and LS174T colorectal carcinoma (200-250% increased length of median survival). The in vivo antitumor effect of the cell-specific immunotoxin plus monensin emulsion was superior to immunotoxin alone or to immunotoxin plus monensin in buffer (P less than 0.03; Mann-Whitney U test). This indicates that delivery of monensin in preformed lipid emulsion may produce a reservoir effect of the ionophore in the peritoneal cavity of tumor-bearing mice. Nonspecific control immunotoxin plus monensin emulsion produced no increase in survival. Long-term tumor-free survival (greater than 150 days versus a median survival of 25 days for controls) of mice bearing microscopic LS174T xenografts was obtained by treatment with anti-human transferrin receptor immunotoxin plus monensin emulsion. Administration of either monensin in buffer or monensin in emulsion without immunotoxin had no significant effect on survival. Monensin in this pharmacologically available form significantly improved the in vivo efficacy of both anti-human transferrin receptor immunotoxin and anti-carcinoembryonic antigen immunotoxin when used as regional therapy.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Cell Line; Cell Survival; Colorectal Neoplasms; Drug Synergism; Emulsions; Half-Life; Humans; Immunotoxins; Mesothelioma; Mice; Mice, Nude; Monensin; Ricin; Transplantation, Heterologous; Tritium