BEZ235 and BKM120 induced pro-apoptotic effects in all cell lines and especially with an increased response in the PI3KCA mutated cells. Our data support the clinical development of these PI3K inhibitors for patients with wild-type or mutated colon cancers.

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 GSK3b and mTOR downstream targets were inhibited with IC 50 values in the nanomolar range. GSK3b signaling inhibition was independent of KRAS, BRAF, and PI3KCA mutation status. While moguntinones alone induced apoptosis only in concentrations >10 mmol/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. Mol Cancer Ther; 13(6); 1399-409. Ó2014 AACR.

<p>PDF file - 42K, Supplementary Figure 3. Effects of Moguntinon 19 on induction of apoptosis during 7 days kinetic.</p>

<p>PDF file - 42K, Supplementary Figure 3. Effects of Moguntinon 19 on induction of apoptosis during 7 days kinetic.</p>

<p>PDF file - 81K, Supplementary Figure 2. Effects of Moguntinon 19 and 13 on cell cycle and induction of apoptosis.</p>