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Gamma secretase inhibitors enhance vincristine-induced apoptosis in T-ALL in a NOTCH-independent manner

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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.

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Abbreviations

T-ALL:

T cell acute lymphoblastic leukemia

GSI:

γ-Secretase inhibitor

PS:

Presenilin

ICN1:

Intracellular domains of human Notch1

DN-MAML1:

Dominant negative mastermind-like 1

VCR:

Vincristine

Ara C:

Cytarabine

MTX:

Methotrexate

ASP:

Asparaginase

Jurkat:

Jurkat-E6

CEM:

CCRF-CEM

P12:

P12-Ichikawa

KOPT:

KOPT-K1

HSB-2:

CCRF-HSB-2

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Acknowledgments

We thank the Louisiana Cancer Research Consortium FACS core for flow cytometry analysis (P20GM103518). This work was supported by NIH Grants P20GM103501 to SOY and R01CA121039 to YSC.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Cellular Immunology, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, 70121, LA, USA

    Sun-Ok Yoon, Mariana C. Zapata, Akannsha Singh, Nakia Spencer & Yong Sung Choi

  2. Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Busan, Korea

    Wol Soon Jo

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  1. Sun-Ok Yoon
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  2. Mariana C. Zapata
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Correspondence to Sun-Ok Yoon.

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Yoon, SO., Zapata, M.C., Singh, A. et al. Gamma secretase inhibitors enhance vincristine-induced apoptosis in T-ALL in a NOTCH-independent manner. Apoptosis 19, 1616–1626 (2014). https://doi.org/10.1007/s10495-014-1029-5

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  • DOI: https://doi.org/10.1007/s10495-014-1029-5

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