Related Experiment Video

Updated: Jun 14, 2025

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

10.6K

Different Strategies to Overcome Resistance to Proteasome Inhibitors-A Summary 20 Years after Their Introduction

Paweł Tyrna1, Grzegorz Procyk2, Łukasz Szeleszczuk3

  • 1Histology and Embryology Students' Science Association, Department of Histology and Embryology, Faculty of Medicine, Warsaw Medical University, Chalubinskiego 5, 02-004 Warsaw, Poland.

International Journal of Molecular Sciences
|August 29, 2024
PubMed

Insights

Proteasome inhibitors (PIs) are key for multiple myeloma (MM), but resistance emerges. This review explores PI resistance mechanisms and strategies, including new drug targets and immunotherapy, to improve MM treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Proteasome inhibitors (PIs) like bortezomib, carfilzomib, and ixazomib are frontline treatments for multiple myeloma (MM).
  • PIs induce cancer cell death by inhibiting proteasomal degradation, leading to protein accumulation.
  • Malignant cells develop resistance to PIs through various mechanisms, limiting therapeutic efficacy.

Purpose of the Study:

  • To review the mechanisms of action of PIs in multiple myeloma.
  • To summarize how multiple myeloma cells develop resistance to proteasome inhibitors.
  • To explore novel strategies for overcoming proteasome inhibitor resistance in multiple myeloma.

Main Methods:

  • Literature review of proteasome inhibitor mechanisms and resistance pathways.
  • Analysis of emerging therapeutic strategies targeting resistance mechanisms.
  • Compilation of potential pharmacological targets investigated in preclinical and clinical studies.

Main Results:

  • Multiple myeloma cells develop resistance to PIs via diverse cellular adaptations.
  • Several strategies are being investigated to overcome PI resistance, including targeting drug efflux, autophagy, stress responses, and survival pathways.
  • Immunotherapy and modulation of the bone marrow microenvironment show promise.

Conclusions:

  • Understanding PI resistance mechanisms is crucial for developing effective MM therapies.
  • Combinatorial approaches and novel drug targets offer potential to overcome resistance.
  • Further research into these strategies may expand therapeutic options and improve patient outcomes in multiple myeloma.
Keywords:
molecular medicineproteasome inhibitorstreatment resistance

More Related Videos

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates09:47

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates

Published on: May 10, 2022

2.5K
Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down08:59

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down

Published on: December 11, 2017

7.2K

Related Concept Videos

Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.3K
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...
4.9K
The Proteasome01:13

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
818
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...
7.5K
The Proteasome Structure01:17

The Proteasome Structure

The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
718
Combined Effects of Drugs: Synergism01:27

Combined Effects of Drugs: Synergism

Synergism is a useful mechanism where combining two or more drugs is more effective than each constituent used alone. Such combinations are also called supra-additive interactions. The drugs collectively enhance the final therapeutic effect by acting on different targets. Another advantage is that the low dose of each constituent drug is sufficient to achieve the desired effect. This helps reduce the duration of therapy and lower the adverse effects of these drugs.
Such synergistic combinations...
3.8K