Related Experiment Video

Updated: Jun 21, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

Small molecule XIAP inhibitors sensitize childhood acute leukemia cells for CD95-induced apoptosis

Sandra Loeder1, Annekathrin Drensek, Irmela Jeremias

  • 1University Children's Hospital, University of Ulm, Ulm, Germany.

International Journal of Cancer
|August 14, 2009
PubMed

Insights

Small molecule inhibitors targeting X-linked inhibitor of apoptosis (XIAP) sensitize childhood acute lymphoblastic leukemia (ALL) cells to apoptosis. This approach enhances treatment efficacy by overcoming apoptosis resistance in leukemia cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Treatment failure in childhood acute lymphoblastic leukemia (ALL) is often linked to resistance to apoptosis (programmed cell death).
  • Developing novel therapeutic strategies to overcome apoptosis resistance is crucial for improving treatment outcomes in pediatric ALL.

Purpose of the Study:

  • To investigate the potential of small molecule inhibitors targeting X-linked inhibitor of apoptosis (XIAP) to sensitize ALL cells to CD95-induced apoptosis.
  • To evaluate the efficacy of XIAP inhibitors in combination with CD95-activating agents on both short-term and long-term survival of ALL cells.
  • To explore the molecular mechanisms underlying the sensitization of ALL cells to apoptosis by XIAP inhibitors.

Main Methods:

  • Utilized small molecule XIAP inhibitors and agonistic anti-CD95 antibodies or MegaFasL in ALL cell lines and primary patient samples.
  • Assessed apoptosis induction, caspase activation, mitochondrial membrane potential, and cytochrome c release.
  • Evaluated the effect on clonogenic survival and compared responses between ALL cells and normal peripheral blood lymphocytes (PBLs).

Main Results:

  • XIAP inhibitors synergistically enhanced CD95-induced apoptosis in ALL cells at subtoxic concentrations.
  • XIAP inhibitors reduced clonogenic survival of ALL cells in combination with MegaFasL, indicating an effect on long-term survival.
  • XIAP inhibitors promoted CD95-mediated caspase activation, mitochondrial dysfunction, and cytochrome c release in a caspase-dependent manner.
  • XIAP inhibitors demonstrated tumor selectivity, with minimal impact on MegaFasL-induced apoptosis in normal PBLs.
  • XIAP inhibitors sensitized primary leukemic blasts from ALL patients to MegaFasL-induced apoptosis.

Conclusions:

  • Small molecule XIAP inhibitors represent a promising therapeutic strategy to enhance CD95-induced apoptosis in childhood acute lymphoblastic leukemia.
  • Targeting XIAP can overcome apoptosis resistance, offering a novel approach to improve treatment efficacy for pediatric ALL.
  • The observed tumor selectivity suggests a favorable therapeutic window for XIAP inhibitors in ALL treatment.

More Related Videos

Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex07:17

Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex

Published on: August 2, 2021

Related Concept Videos

The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...