Vincristine resistance in relapsed neuroblastoma can be efficiently overcome by Smac mimetic LCL161 treatment
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Vincristine resistance in relapsed neuroblastoma can be efficiently overcome by Smac mimetic LCL161 treatment. / Frommann, Kristin; Appl, Birgit; Hundsdoerfer, Patrick; Reinshagen, Konrad; Eschenburg, Georg.
In: J PEDIATR SURG, Vol. 53, No. 10, 10.2018, p. 2059-2064.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Vincristine resistance in relapsed neuroblastoma can be efficiently overcome by Smac mimetic LCL161 treatment
AU - Frommann, Kristin
AU - Appl, Birgit
AU - Hundsdoerfer, Patrick
AU - Reinshagen, Konrad
AU - Eschenburg, Georg
N1 - Copyright © 2018. Published by Elsevier Inc.
PY - 2018/10
Y1 - 2018/10
N2 - PURPOSE: In spite of good initial therapy response neuroblastomas often spread to distant organs or relapse after periods of remission. Dysregulation of apoptosis, a hallmark of cancer, is often effected by elevated levels of antiapoptotic signals leading to resistance against chemotherapeutic drugs. Inhibitors of apoptosis proteins (IAPs) are crucial cellular apoptosis regulators. Targeting IAPs with Smac mimetics has been demonstrated as a promising strategy for treatment of neuroblastoma and other tumors.METHODS: In paired neuroblastoma cell lines, obtained from the same patient at time of diagnosis (CHLA-15) and postchemotherapy during progressive disease (CHLA-20), expression of crucial IAPs was determined. Furthermore, effects of vincristine on viability, cytotoxicity, apoptosis induction and caspase-3/7 activation were determined.RESULTS: Cellular IAP-1 (cIAP-1) and X-linked IAP (XIAP) expression was increased in cell line CHLA-20. Moreover, biological effects of vincristine were significantly lower in these cells. Treatment of cells with Smac mimetic LCL161 increased the effects of vincristine in CHLA-15 cells and more importantly was able to overcome vincristine resistance in CHLA-20 cells.CONCLUSIONS: These findings demonstrate the potential of Smac mimetics for the development of novel therapeutic approaches for the treatment of relapsed/resistant neuroblastoma.
AB - PURPOSE: In spite of good initial therapy response neuroblastomas often spread to distant organs or relapse after periods of remission. Dysregulation of apoptosis, a hallmark of cancer, is often effected by elevated levels of antiapoptotic signals leading to resistance against chemotherapeutic drugs. Inhibitors of apoptosis proteins (IAPs) are crucial cellular apoptosis regulators. Targeting IAPs with Smac mimetics has been demonstrated as a promising strategy for treatment of neuroblastoma and other tumors.METHODS: In paired neuroblastoma cell lines, obtained from the same patient at time of diagnosis (CHLA-15) and postchemotherapy during progressive disease (CHLA-20), expression of crucial IAPs was determined. Furthermore, effects of vincristine on viability, cytotoxicity, apoptosis induction and caspase-3/7 activation were determined.RESULTS: Cellular IAP-1 (cIAP-1) and X-linked IAP (XIAP) expression was increased in cell line CHLA-20. Moreover, biological effects of vincristine were significantly lower in these cells. Treatment of cells with Smac mimetic LCL161 increased the effects of vincristine in CHLA-15 cells and more importantly was able to overcome vincristine resistance in CHLA-20 cells.CONCLUSIONS: These findings demonstrate the potential of Smac mimetics for the development of novel therapeutic approaches for the treatment of relapsed/resistant neuroblastoma.
KW - Journal Article
U2 - 10.1016/j.jpedsurg.2018.01.012
DO - 10.1016/j.jpedsurg.2018.01.012
M3 - SCORING: Journal article
C2 - 29455885
VL - 53
SP - 2059
EP - 2064
JO - J PEDIATR SURG
JF - J PEDIATR SURG
SN - 0022-3468
IS - 10
ER -
