title: Identification of novel compounds that enhance colon cancer cell sensitivity to inflammatory apoptotic ligands.
abstract: Immune and inflammatory death ligands expressed within neoplastic tissue could potentially target apoptosis to transformed cells. To develop approaches that accentuate the anti-cancer potential of the inflammatory response, the Chembridge DIVERSet (TM) library was screened for compounds that accentuated apoptosis in a strictly TNF-dependent manner. We identified a number of novel compounds with this activity, the most active of these, AK3 and AK10, sensitized colon cancer cells to TNF at 0.5 μM and 2 μM, respectively, without inducing apoptosis on their own. The activity of these compounds was structure-dependent and general, as they accentuated cell death by TNF or Fas ligation in multiple colon cancer cell lines. Both AK3 and AK10 arrested cells in mitosis, with live cell imaging indicating that mitotically arrested cells were the source of apoptotic bodies. AK3 accentuated caspase-8 and caspase-9 activation with little effect on NFκB target gene activation. Enhanced caspase activation corresponded to an increased expression of TNFR1 on the cell surface. To determine the general interplay between mitotic arrest and TNF sensitivity, Aurora kinase (MLN8054 and MLN8237) and PLK1 (BI2536) inhibitors were tested for their ability to sensitize cells to TNF. PLK1 inhibition was particularly effective and influenced TNFR1 surface presentation and caspase cleavage like AK3, even though it arrested mitosis at an earlier stage. We propose that AK3 and AK10 represent a new class of mitotic inhibitor and that selected mitotic inhibitors may be useful for treating colon cancers or earlier lesions that have a high level of inflammatory cell infiltrate.
authors: Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA.
authors: Avijeet S
authors: AS
authors: Chopra
authors: Anton
authors: A
authors: Kuratnik
authors: Eric W
authors: EW
authors: Scocchera
authors: Dennis L
authors: DL
authors: Wright
authors: Charles
authors: C
authors: Giardina
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002457:Cell Extracts / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004357:Drug Synergism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002457:Cell Extracts; D008024:Ligands; D014409:Tumor Necrosis Factor-alpha
keywords: Fas; PLK1; TNF; TNFR1; apoptosis; caspases; colon cancer; mitosis; small molecules
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