{"id":{"repo_id":"buffalo","oai_identifier":"oai:ubir.buffalo.edu:10477/80028"},"canonical_url":"https://search.dev.ndltd.org/etd/buffalo/oai:ubir.buffalo.edu:10477/80028","repository":{"repo_id":"buffalo","name":"Buffalo","base_url":"https://ubir.buffalo.edu/oai/request"},"display":{"title":"Targeting X-linked Inhibitor of Apoptosis Protein to Overcome Rituximab/Chemotherapy Resistance in B-cell Lymphomas","abstract":"M.S.","abstract_html":"M.S.","abstract_has_math":false,"creators":["Khan, Sumera"],"institution":"State University of New York at Buffalo","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Hernandez-Ilizaliturri, Francisco","Roswell Park"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-07-30T15:11:57Z","date_published":"2019-07-30T15:11:57Z","updated_at":"2026-07-27T19:05:23Z","subjects":["immunology","oncology","microbiology","cancer sciences"],"languages":["eng"],"rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10477/80028","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Hernandez-Ilizaliturri, Francisco","Roswell Park"]},{"key":"dc:creator","label":"Author","values":["Khan, Sumera"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2019-07-30T15:11:57Z","2019","2019-05-17 13:03:36"]},{"key":"dc:publisher","label":"Institution","values":["State University of New York at Buffalo"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["immunology","oncology","microbiology","cancer sciences"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/10477/80028"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["M.S.","ABSTRACTTargeting X-linked Inhibitor of Apoptosis Protein (XIAP) to Overcome Rituximab/ Chemotherapy Resistance in B-Cell Lymphomas.The addition of Rituximab to front-line therapy has improved clinical outcomes in diffuse large B-cell lymphoma (DLBCL), but it has also altered the biology of relapsed/refractory disease. To better understand the mechanisms responsible for Rituximab associated chemotherapy cross-resistance our group developed and characterized several Rituximab resistant cell lines (RRCL). We previously demonstrated using SiRNA interference, that X-linked inhibitor of apoptosis (XIAP) is critical for chemotherapy sensitivity and survival in RRCL. Using MX69, a dual inhibitor of MDM2and XIAP that indirectly downregulates XIAP, in pre-clinical testing we downregulated XIAP to evaluate whether this strategy can help overcome rituximab resistance. MX69 affects XIAP levels by its effects on the ubiquitination and degradation of endogenous MDM-2, resulting in decreased XIAP translation which results in activation of caspase 3, 7 and 9, and cleavage of PARP enhancing apoptosis of cancer cells. In our current work, we pharmacologically inhibited XIAP in lymphoma pre-clinical models using MX69.In vitro, a panel of Burkitt's Lymphoma (BL, including RRCL), germinal center B-cell (GCB)-DLBCL (including RRCL), activated B-cell (ABC)-DLBCL, Mantle cell Lymphoma (MCL) and Pre-B cell Leukemia cell lines were exposed to MX69 as a single agent (0-80uM) over 24, 48, 72 hrs. Half maximal inhibitory concentrations(IC50)were calculated for each cell line, to define the single agent activity of MX69 as an antilymphoma agent. Western blotting studies confirmed the mechanism of action for the compound with downregulation of Mdm2, XIAP and changes in P53 and PARP, following in vitro MX69 exposure (at IC50 doses) for 24 hrs. Induction of apoptosis was observed by Annexin V/propidium iodine staining. Subsequently, in order to test the potential for MX69 to enhance chemosensitivity, cell lines were exposed to MX69 (0-80 uM), in combination with doxorubicin (0-1uM), cytarabine (0-50uM), vincristine (0-10nM), etoposide (0-50uM), carboplatin (0-20uM), ixazomib (0-1.5uM), ibrutinib (0-20uM) and venetoclax (0-10uM) for 48 hours."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Targeting X-linked Inhibitor of Apoptosis Protein to Overcome Rituximab/Chemotherapy Resistance in B-cell Lymphomas"]}]}],"canonical_facts":{"dc:contributor":["Hernandez-Ilizaliturri, Francisco","Roswell Park"],"dc:creator":["Khan, Sumera"],"dc:date":["2019-07-30T15:11:57Z","2019","2019-05-17 13:03:36"],"dc:description":["M.S.","ABSTRACTTargeting X-linked Inhibitor of Apoptosis Protein (XIAP) to Overcome Rituximab/ Chemotherapy Resistance in B-Cell Lymphomas.The addition of Rituximab to front-line therapy has improved clinical outcomes in diffuse large B-cell lymphoma (DLBCL), but it has also altered the biology of relapsed/refractory disease. To better understand the mechanisms responsible for Rituximab associated chemotherapy cross-resistance our group developed and characterized several Rituximab resistant cell lines (RRCL). We previously demonstrated using SiRNA interference, that X-linked inhibitor of apoptosis (XIAP) is critical for chemotherapy sensitivity and survival in RRCL. Using MX69, a dual inhibitor of MDM2and XIAP that indirectly downregulates XIAP, in pre-clinical testing we downregulated XIAP to evaluate whether this strategy can help overcome rituximab resistance. MX69 affects XIAP levels by its effects on the ubiquitination and degradation of endogenous MDM-2, resulting in decreased XIAP translation which results in activation of caspase 3, 7 and 9, and cleavage of PARP enhancing apoptosis of cancer cells. In our current work, we pharmacologically inhibited XIAP in lymphoma pre-clinical models using MX69.In vitro, a panel of Burkitt's Lymphoma (BL, including RRCL), germinal center B-cell (GCB)-DLBCL (including RRCL), activated B-cell (ABC)-DLBCL, Mantle cell Lymphoma (MCL) and Pre-B cell Leukemia cell lines were exposed to MX69 as a single agent (0-80uM) over 24, 48, 72 hrs. Half maximal inhibitory concentrations(IC50)were calculated for each cell line, to define the single agent activity of MX69 as an antilymphoma agent. Western blotting studies confirmed the mechanism of action for the compound with downregulation of Mdm2, XIAP and changes in P53 and PARP, following in vitro MX69 exposure (at IC50 doses) for 24 hrs. Induction of apoptosis was observed by Annexin V/propidium iodine staining. Subsequently, in order to test the potential for MX69 to enhance chemosensitivity, cell lines were exposed to MX69 (0-80 uM), in combination with doxorubicin (0-1uM), cytarabine (0-50uM), vincristine (0-10nM), etoposide (0-50uM), carboplatin (0-20uM), ixazomib (0-1.5uM), ibrutinib (0-20uM) and venetoclax (0-10uM) for 48 hours."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/10477/80028"],"dc:language":["eng"],"dc:publisher":["State University of New York at Buffalo"],"dc:rights":["Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.","Copyright retained by author."],"dc:subject":["immunology","oncology","microbiology","cancer sciences"],"dc:title":["Targeting X-linked Inhibitor of Apoptosis Protein to Overcome Rituximab/Chemotherapy Resistance in B-cell Lymphomas"],"dc:type":["Thesis","Text"]},"updated_at":"2026-07-27T19:05:23Z"}