Intrinsic and chemo-sensitizing activity of SMAC-mimetics on high-risk childhood acute lymphoblastic leukemia

Cell Death & Disease
M SchirmerK-M Debatin

Abstract

SMAC-mimetics represent a targeted therapy approach to overcome apoptosis resistance in many tumors. Here, we investigated the efficacy of the SMAC-mimetic BV6 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In ALL cell lines, intrinsic apoptosis sensitivity was associated with rapid cIAP degradation, NF-κB activation, TNF-α secretion and induction of an autocrine TNF-α-dependent cell death loop. This pattern of responsiveness was also observed upon ex vivo analysis of 40 primograft BCP-ALL samples. Treatment with BV6 induced cell death in the majority of ALL primografts including leukemias with high-risk and poor-prognosis features. Inhibition of cell death by the TNF receptor fusion protein etanercept demonstrated that BV6 activity is dependent on TNF-α. In a preclinical NOD/SCID/huALL model of high-risk ALL, marked anti-leukemia effectivity and significantly prolonged survival were observed upon BV6 treatment. Interestingly, also in vivo, intrinsic SMAC-mimetic activity was mediated by TNF-α. Importantly, BV6 increased the effectivity of conventional induction therapy including vincristine, dexamethasone and asparaginase leading to prolonged remission induction. These data suggest SMAC-mimetics as an important ad...Continue Reading

References

Jan 13, 2006·The New England Journal of Medicine·Ching-Hon Pui, William E Evans
Jun 19, 2007·Apoptosis : an International Journal on Programmed Cell Death·Allison M HunterRobert G Korneluk
May 20, 2008·Cell·Lai WangXiaodong Wang
May 23, 2008·Cytokine & Growth Factor Reviews·Avi Ashkenazi
Nov 13, 2008·International Journal of Cancer. Journal International Du Cancer·Simone Fulda
Aug 5, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Aaron D SchimmerMichael Andreeff
Oct 14, 2009·Current Opinion in Cell Biology·Dirk Brenner, Tak W Mak
Jan 26, 2010·Drug Discovery Today·Raimund MannholdEmanuele Carosati
Aug 11, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Thorsten ZenzStephan Stilgenbauer
Oct 27, 2010·Human Cell·Hans G Drexler, Roderick A F Macleod
Jan 12, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Ching-Hon PuiRobert J Arceci
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Jun 18, 2011·Pediatric Blood & Cancer·Peter J HoughtonMalcolm A Smith
Nov 19, 2011·Cell Death and Differentiation·M Darding, P Meier
Feb 2, 2012·Nature Reviews. Drug Discovery·Simone Fulda, Domagoj Vucic
Aug 10, 2012·Cell Death & Disease·M QueudevilleL H Meyer
Apr 27, 2013·Leukemia Research·Cinzia ScavulloGiorgio Lambertenghi Deliliers
Oct 5, 2013·OncoTargets and Therapy·Laurence DubrezValérie Glorian
Jan 1, 2013·Cells·Jean Berthelet, Laurence Dubrez

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Citations

Feb 19, 2017·Biochemical and Biophysical Research Communications·Klaus-Michael Debatin
Oct 27, 2017·Apoptosis : an International Journal on Programmed Cell Death·Mervat S MohamedAyat G Ali
Oct 28, 2019·Cancers·Zhang'e ChooZhi Xiong Chen
Nov 22, 2019·International Journal of Cancer. Journal International Du Cancer·Julia ZinngrebeKlaus-Michael Debatin
Apr 21, 2017·Apoptosis : an International Journal on Programmed Cell Death·Rama RathoreDietrich Büsselberg
Nov 14, 2019·BMC Cancer·Manuela SalvucciJochen H M Prehn
Nov 23, 2017·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Bonnie WilliamsTania Crotti
Jul 31, 2019·Cell Death & Disease·Felix SeyfriedLüder Hinrich Meyer
Jun 16, 2016·Cancer Research·Jennifer RichmondRichard B Lock
Jul 1, 2020·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Nir Shahar, Sarit Larisch
Sep 21, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Dorien ClarisseKarolien De Bosscher

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Methods Mentioned

BETA
ubiquitination
immunoprecipitation
xenografting
xenograft
xenografts
flow cytometry
transfection

Software Mentioned

GraphPad
SPSS
Prism

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