Polysulfanes show chemopreventive effects against gastrointestinal tumors We identified diallyl tetrasulfide and its derivative dibenzyl tetrasulfide DBTTS to be mitotic inhibitors and apoptosis inducers Here we translate their application in colorectal cancer CRC MALDI-TOF-MS analysis identified both compounds as reversible tubulin binders validated by in cellulo -tubulin degradation BRAF V600E -mutated HT-29 cells were resistant to DBTTS as evidenced by mitotic arrest for 48 h prior to apoptosis induction compared to KRAS G12V -mutated SW480 620 cells which committed to death earlier The prolonged mitotic block correlated with autophagy impairment and p62 protein accumulation in HT-29 but not in SW480 620 cells whereas siRNA-mediated p62 inhibition sensitized HT-29 cells to death In silico analysis with 484 colorectal cancer patients associated higher p62 expression and reduced autophagic flux with greater overall survival Accordingly we hypothesized that DBTTS targets CRC survival death through autophagy interference in cell types with differential autophagic capacities We confirmed the therapeutic potential of DBTTS by the inhibition of spheroid and colony formation capacities in CRC cells as well as in HT-29 zebrafish xenografts in vivo
Polysulfanes show chemopreventive effects against gastrointestinal tumors We identified diallyl tetrasulfide and its derivative dibenzyl tetrasulfide DBTTS to be mitotic inhibitors and apoptosis inducers Here we translate their application in colorectal cancer CRC MALDI-TOF-MS analysis identified both compounds as reversible tubulin binders validated by in cellulo -tubulin degradation BRAF V600E -mutated HT-29 cells were resistant to DBTTS as evidenced by mitotic arrest for 48 h prior to apoptosis induction compared to KRAS G12V -mutated SW480 620 cells which committed to death earlier The prolonged mitotic block correlated with autophagy impairment and p62 protein accumulation in HT-29 but not in SW480 620 cells whereas siRNA-mediated p62 inhibition sensitized HT-29 cells to death In silico analysis with 484 colorectal cancer patients associated higher p62 expression and reduced autophagic flux with greater overall survival Accordingly we hypothesized that DBTTS targets CRC survival death through autophagy interference in cell types with differential autophagic capacities We confirmed the therapeutic potential of DBTTS by the inhibition of spheroid and colony formation capacities in CRC cells as well as in HT-29 zebrafish xenografts in vivo
A new series of N-aryl-N -3 4-dihydro-2 2-dimethyl-2H-1-benzopyran-4-yl ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells Based on computational docking combined to in vitro sirtuin 1 2 inhibition assays we selected compound 18 R S-N-3-cyanophenyl-N - 6-tert-butoxycarbonylamino-3 4-dihydro-2 2-dimethyl-2H-1-benzopyran-4-yl urea which displays a potent antiproliferative activity on various glioma cell types assessed by quantitative videomicroscopy eventually triggering senescence The impact on normal glial cells was lower with a selectivity index 10 Furthermore human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase HDAC class III sirtuins 1 and 2 SIRT1 2 by quantifying acetylation levels of histone and non-histone proteins The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models Eventually the anticancer potential of 18 was validated in 3D glioblastoma spheroids and in vivo by zebrafish xenografts In summary compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors
A new series of N-aryl-N -3 4-dihydro-2 2-dimethyl-2H-1-benzopyran-4-yl ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells Based on computational docking combined to in vitro sirtuin 1 2 inhibition assays we selected compound 18 R S-N-3-cyanophenyl-N - 6-tert-butoxycarbonylamino-3 4-dihydro-2 2-dimethyl-2H-1-benzopyran-4-yl urea which displays a potent antiproliferative activity on various glioma cell types assessed by quantitative videomicroscopy eventually triggering senescence The impact on normal glial cells was lower with a selectivity index 10 Furthermore human U373 and Hs683 glioblastoma cell lines served to demonstrate the inhibitory activity of 18 against histone deacetylase HDAC class III sirtuins 1 and 2 SIRT1 2 by quantifying acetylation levels of histone and non-histone proteins The translational potential of 18 was validated by an NCI-60 cell line screen and validation of growth inhibition of drug resistant cancer cell models Eventually the anticancer potential of 18 was validated in 3D glioblastoma spheroids and in vivo by zebrafish xenografts In summary compound 18 is the first representative of a new class of SIRT inhibitors opening new perspectives in the medicinal chemistry of HDAC inhibitors