Related Experiment Video

Updated: Jun 29, 2025

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
08:59

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

New Insights into Chemoresistance Mediated by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common

Tatyana Grigoreva1, Aleksandra Sagaidak1, Daria Novikova1

  • 1Laboratory of Molecular Pharmacology, St. Petersburg State Institute of Technology (Technical University), St. Petersburg 190013, Russia.

Biomedicines
|March 28, 2024
PubMed

Insights

Targeted anticancer drugs like Mdm2 inhibitors show lower risks of secondary chemoresistance compared to traditional cytostatics. Nutlin-3a activates cellular defenses but enhances susceptibility to other drugs, indicating a safer therapeutic approach.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Targeting the Mdm2-p53 interaction is a key anticancer strategy.
  • Secondary chemoresistance development requires further investigation for targeted therapies.
  • Comparing resistance mechanisms to Mdm2 inhibitors and cytostatics is crucial.

Purpose of the Study:

  • To compare secondary chemoresistance development in cells treated with an Mdm2 inhibitor (Nutlin-3a) versus paclitaxel.
  • To elucidate the mechanisms underlying chemoresistance to Mdm2 inhibition.
  • To assess the safety and efficacy of Mdm2 inhibitors regarding chemoresistance.

Main Methods:

  • Generation of drug-resistant cell lines through long-term cultivation.
  • Comparative analysis of resistance profiles between Mdm2 inhibitor and paclitaxel treatments.
  • Investigation of cellular machinery and efflux mechanisms affected by Nutlin-3a.

Main Results:

  • Mdm2 inhibitors demonstrate lower secondary chemoresistance development compared to cytostatics.
  • Nutlin-3a impacts both p53-mediated pathways and ABC-mediated efflux.
  • Despite activating defense mechanisms, Nutlin-3a increases tumor cell susceptibility to other drugs.

Conclusions:

  • Targeted Mdm2 inhibition presents a fundamentally lower risk of chemoresistance than cytotoxic therapy.
  • Mdm2 inhibitors offer a potentially safer anticancer therapeutic strategy.
  • Understanding dual-action resistance mechanisms is key for optimizing targeted cancer treatments.
Keywords:
BCRPMDRNutlin-3aP-glycoproteincytostaticsdrug resistancepaclitaxel

More Related Videos

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts10:27

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

Published on: July 25, 2020

7.2K
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms08:46

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

Published on: December 9, 2015

10.6K

Related Concept Videos

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...
7.6K
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
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.5K
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.6K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.7K