Tubulin-binding anticancer polysulfides induce cell death via mitotic arrest and autophagic interference in colorectal cancer. (1st December 2017)

• Record Type: Journal Article
• Authors: Yagdi Efe, Esma; Mazumder, Aloran; Lee, Jin-Young; Gaigneaux, Anthoula; Radogna, Flavia; Nasim, Muhammad Jawad; Christov, Christo; Jacob, Claus; Kim, Kyu-Won; Dicato, Mario; Chaimbault, Patrick; Cerella, Claudia; Diederich, Marc
• Is Part Of: Cancer letters. Volume 410(2017)
• Page Start: 139
• Page End: 157
• Publication Date: 2017-12-01
• Subjects: Diallyl sulfide -- Mitotic arrest -- Cell death -- Autophagic flux -- Zebrafish xenografts; Baf bafilomycin A1 -- BRAF v-Raf murine sarcoma viral oncogene homolog B -- CFAs colony formation assays -- CHCA α-cyano-4-hydroxy-cinnamic acid -- CHX cycloheximide -- CIMP CpG island methylator phenotype -- CIN chromosomal instability -- CRC colorectal cancer -- DATTS diallyl tetrasulfide -- DBTTS dibenzyl tetrasulfide -- DHB 2, 5-dihydroxybenzoic acid -- EGFR epithelial growth factor receptor -- FDR false discovery rate -- GO gene ontology -- HO heme-oxygenase -- KEAP1 kelch-like ECH-associated protein 1 -- KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog -- LC3 microtubule-associated protein light chain 3 -- MALDI-TOF-MS matrix assisted laser desorption ionization-time of flight-mass spectrometry -- MSI microsatellite instability -- MTA microtubule-altering agent -- mTOR mammalian target of rapamycin -- NRF2 nuclear factor (erythroid-derived 2)-like 2 -- NF-κB nuclear factor-kappa B -- OSC organic sulfur compound -- PGP p-glycoprotein -- PI propidium iodide -- PIK3CA phosphatidylinositol-4, 5-bisphosphate 3-kinase -- PTEN phosphatase and tensin homolog -- Q-RT-PCR quantitative real-time polymerase chain reaction -- ROS reactive oxygen species -- SD standard deviation -- siRNA small inhibitor RNA -- TEM transmission electron microscopy -- TFA trifluoroacetic acid -- TP53 tumor protein 53 -- TREAT t-tests relative to a threshold; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.09.011
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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 α-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 .