title: Gamma secretase inhibitors enhance vincristine-induced apoptosis in T-ALL in a NOTCH-independent manner.
abstract: Activating mutations in the NOTCH1 gene are found in over 50 % of T-ALL cases. Since Notch signaling contributes to the leukemia cell survival and growth, targeting Notch signaling using γ-secretase inhibitors (GSI) has been proposed as a molecularly targeted therapy for the treatment of T-ALL. However, not all T-ALL with NOTCH1 activating mutations respond to GSI treatment. We examined whether GSI could enhance the cytotoxic effect of anti-leukemic agents in the GSI-resistant T-ALL cells although GSI does not have anti-tumor effect as a single agent. GSI significantly increased cell death induced by Vincristine (VCR) but not other anti-leukemic drugs (Methotrexate, Asparaginase, and Cytarabine). The GSI effect in enhancing VCR efficacy was not the result of inhibition of Notch signaling. GSI augmented VCR-induced mitotic arrest, followed by apoptosis. GSI accelerated VCR-triggered loss of mitochondrial membrane potential and caspase-mediated apoptosis. Our finding suggests that GSI has other functions besides inhibiting Notch signaling in T-ALL and incorporating GSI into the conventional regimen containing VCR may offer therapeutic advantage by potentiating VCR treatment in leukemia patients.
authors.affiliation: Laboratory of Cellular Immunology, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, 70121, LA, USA, syoon75@gmail.com.
authors.forename: Sun-Ok
authors.initials: SO
authors.lastname: Yoon
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Zapata
authors.forename: Akannsha
authors.initials: A
authors.lastname: Singh
authors.forename: Wol Soon
authors.initials: WS
authors.lastname: Jo
authors.forename: Nakia
authors.initials: N
authors.lastname: Spencer
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Choi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D051880:Receptors, Notch / Q000378:metabolism*; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D014750:Vincristine; D053829:Amyloid Precursor Protein Secretases; D020169:Caspases