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.