Related Experiment Video

Updated: Oct 18, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.4K

Caspase-8 Regulates the Antimyeloma Activity of Bortezomib and Lenalidomide

Liang Zhou1, Xiangao Huang2, Ruben Niesvizky2

  • 1Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Jiangsu, China (L.Z., G.X.); Department of Pathology and Laboratory Medicine (X.H.) and Department of Medicine (R.N.), Weill Cornell Medicine, New York, New York; Department of Oncology, Haian Hospital of Traditional Chinese Medicine, Haian, Jiangsu, China (Z.P.) liangzhou@suda.edu.cn gux2002@suda.edu.cn.

The Journal of Pharmacology and Experimental Therapeutics
|September 30, 2021
PubMed

Insights

Bortezomib (Btz) treatment causes caspase-8 (CASP-8) to cleave cereblon (CRBN). Inhibiting CASP-8 enhances the effectiveness of Btz and lenalidomide (Len) combination therapy for multiple myeloma.

Area of Science:

  • Molecular oncology
  • Drug resistance mechanisms
  • Cancer therapeutics

Background:

  • Multiple myeloma is treated with proteasome inhibitors and immunomodulatory drugs (IMiDs).
  • Combination therapies show high response rates but frequently lead to drug resistance.
  • Novel therapeutic strategies are needed to overcome resistance in multiple myeloma.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying drug resistance in multiple myeloma.
  • To explore novel therapeutic targets for enhancing existing multiple myeloma treatments.

Main Methods:

  • Investigated the effect of bortezomib (Btz) on cereblon (CRBN) cleavage.
  • Identified caspase-8 (CASP-8) as the enzyme responsible for CRBN cleavage.
  • Assessed the impact of CASP-8 inhibition or depletion on CRBN cleavage and therapeutic efficacy.

Main Results:

  • Bortezomib (Btz) treatment induces cereblon (CRBN) cleavage mediated by caspase-8 (CASP-8).
  • Inhibition or genetic depletion of CASP-8 significantly reduced CRBN cleavage following Btz treatment.
  • Blocking CASP-8 activity potentiated the anti-myeloma effects of lenalidomide (Len) in combination with Btz.

Conclusions:

  • Caspase-8 activation by bortezomib leads to cereblon cleavage, potentially impacting lenalidomide efficacy.
  • Targeting caspase-8 presents a promising strategy to enhance combination therapy for multiple myeloma.
  • Administration of caspase-8 inhibitors could improve treatment outcomes for patients with multiple myeloma.

More Related Videos

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity07:09

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Published on: January 7, 2019

7.6K
Evaluation of Caspase Activation to Assess Innate Immune Cell Death10:23

Evaluation of Caspase Activation to Assess Innate Immune Cell Death

Published on: January 20, 2023

3.4K

Related Concept Videos

Caspases01:24

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
12.8K
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...
7.1K
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...
6.8K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.2K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.0K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
2.3K