title: The BH3-mimetic obatoclax reduces HIF-1α levels and HIF-1 transcriptional activity and sensitizes hypoxic colon adenocarcinoma cells to 5-fluorouracil.
abstract: Activation of hypoxia-inducible factor (HIF)-1 is a feature of hypoxic solid tumors that has been associated with drug resistance, mainly due to disruption of Bcl-2 family dynamics. Resetting the balance in favor of proapoptotic family members is an attractive therapeutic goal that has been pursued by developing BH3-mimetic compounds. In the present study we evaluated the response of human colon adenocarcinoma cells to the BH3-mimetic obatoclax (OBX), in terms of growth arrest, apoptosis and autophagy, in the presence or absence of HIF-1α-stabilizing conditions; its possible effect on HIF-1α expression and HIF-1 activity; and the possibility to improve the response of colon cancer cells to cytotoxic chemotherapeutics by combining them with OBX. Colon cancer cell response to the BH3-mimetic was unmodified by HIF-1 activation and OBX induced a decrease in HIF-1α protein levels and HIF-1 transcriptional activity, probably by decreasing HIF-1α synthesis and facilitating a VHL-independent proteasomal degradation pathway. Finally, a chemosensitizing effect of OBX with respect to 5-fluorouracil or oxaliplatin treatment was observed, highlighting the possibility that patients with hypoxic colon tumors might benefit from combined regimens including OBX.
authors.affiliation: Department of Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
authors.forename: Marzia B
authors.initials: MB
authors.lastname: Gariboldi
authors.affiliation: Department of Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Taiana
authors.affiliation: Department of Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Bonzi
authors.affiliation: Department of Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Craparotta
authors.affiliation: Department of Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Giovannardi
authors.affiliation: Department of Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Department of Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy. Electronic address: elena.monti@uninsubria.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Monti
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007211:Indoles; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011758:Pyrroles; C520962:obatoclax; D005472:Fluorouracil
keywords: 5-Fluorouracil; Colon cancer; Drug resistance; HIF-1; Obatoclax; Oxaliplatin