title: Moguntinones--new selective inhibitors for the treatment of human colorectal cancer.
abstract: 3-Indolyl and 3-azaindolyl-4-aryl maleimide derivatives, called moguntinones (MOG), have been selected for their ability to inhibit protein kinases associated with angiogenesis and induce apoptosis. Here, we characterize their mode of action and their potential clinical value in human colorectal cancer in vitro and in vivo. MOG-19 and MOG-13 were characterized in vitro using kinase, viability, and apoptosis assays in different human colon cancer (HT-29, HCT-116, Caco-2, and SW480) and normal colon cell lines (CCD-18Co, FHC, and HCoEpiC) alone or in combination with topoisomerase I inhibitors. Intracellular signaling pathways were analyzed by Western blotting. To determine their potential to inhibit tumor growth in vivo, the human HT-29 tumor xenograft model was used. Moguntinones prominently inhibit several protein kinases associated with tumor growth and metastasis. Specific signaling pathways such as GSK3β and mTOR downstream targets were inhibited with IC(50) values in the nanomolar range. GSK3β signaling inhibition was independent of KRAS, BRAF, and PI3KCA mutation status. While moguntinones alone induced apoptosis only in concentrations >10 μmol/L, MOG-19 in combination with topoisomerase I inhibitors induced apoptosis synergistically at lower concentrations. Consistent with in vitro data, MOG-19 significantly reduced tumor volume and weight in combination with a topoisomerase I inhibitor in vivo. Our in vitro and in vivo data present significant proapoptotic, antiangiogenic, and antiproliferative effects of MOG-19 in different human colon cancer cells. Combination with clinically relevant topoisomerase I inhibitors in vitro and xenograft mouse model demonstrate a high potency of moguntinones to complement and improve standard chemotherapy options in human colorectal cancer.
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Maderer
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Plutizki
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: Kramb
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Göpfert
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Linnig
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Khillimberger
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ganser
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Lauermann
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Dannhardt
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.affiliation: Authors' Affiliations: Departments of Internal Medicine I and Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Mainz, Germany markus.moehler@unimedizin-mainz.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Moehler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008301:Maleimides / Q000008:administration & dosage*; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D008301:Maleimides; D059004:Topoisomerase I Inhibitors; C000595234:moguntinone 19; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases