Related Experiment Video

Updated: Apr 5, 2026

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

14.0K

Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents

Yun-Kai Zhang1, Hengyuan Zhang2, Guan-Nan Zhang1

  • 1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.

Oncotarget
|August 23, 2015
PubMed

Insights

A novel compound, ORA, effectively reverses multidrug resistance in cancer by inhibiting the ABCB1 transporter. This finding offers potential new strategies for overcoming chemotherapy failure in cancer treatment.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • Overexpression of ATP-Binding Cassette (ABC) transporters, particularly ABCB1, is a primary cause of multidrug resistance (MDR) in cancer.
  • This resistance leads to chemotherapy failure, necessitating novel therapeutic strategies to overcome MDR.

Purpose of the Study:

  • To investigate the potential of (20S, 24R/S)-epoxy-12β, 25-dihydroxy-dommarane-3β-amine (ORA and OSA), semi-synthetic ocotillol analogue epimers, in inhibiting the ABCB1 transporter.
  • To determine if ORA and OSA can reverse ABCB1-mediated multidrug resistance in cancer cells.

Main Methods:

  • In-vitro study using ABCB1-overexpressing cell lines (SW620/Ad300 and HEK/ABCB1).
  • Assessed the reversal of resistance to paclitaxel and vincristine by ORA and OSA.
  • Measured intracellular accumulation of [3H]-paclitaxel.
  • Evaluated ABCB1 protein expression and subcellular localization.
  • Performed ABCB1 ATPase activity assays and molecular docking studies.

Main Results:

  • ORA (1 μM and 3 μM) significantly reversed paclitaxel and vincristine resistance in ABCB1-overexpressing cells; OSA showed no significant effect.
  • ORA (3 μM) increased intracellular [3H]-paclitaxel accumulation by suppressing ABCB1 efflux.
  • Neither ORA nor OSA altered ABCB1 protein expression or localization.
  • ORA demonstrated a stronger stimulatory effect on ABCB1 ATPase activity and a higher docking score within the ABCB1 transmembrane domain compared to OSA.

Conclusions:

  • ORA effectively reverses ABCB1-mediated multidrug resistance by competitively inhibiting the drug efflux function of the ABCB1 transporter.
  • ORA shows promise as a therapeutic agent to enhance chemotherapy efficacy in multidrug-resistant cancers.
  • The mechanism involves direct interaction with and inhibition of ABCB1 activity, rather than altering its expression or localization.
Keywords:
ABC transporterABCB1ginsenosidemultidrug resistanceocotillol-type triterpenoid derivatives

More Related Videos

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

11.3K
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

7.7K

Related Concept Videos

Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters01:16

Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters

The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...
126
Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers01:12

Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers

Class III antiarrhythmic drugs are a group of medications that can prolong action potentials in the heart. They achieve this by blocking potassium channels or enhancing inward currents from sodium channels. However, these drugs have a unique property of "reverse use-dependence," which is most pronounced at slower heart rates and can lead to torsades de pointes—a specific type of arrhythmia. However, it is essential to note that excessive QT interval prolongation—a measure of...
3.0K
Drug Elimination by Renal Route: Tubular Reabsorption01:22

Drug Elimination by Renal Route: Tubular Reabsorption

During the process of renal excretion, as the glomerular filtrate progresses to the distal convoluted tubule (DCT), drugs that are highly permeable, lipophilic, and nonionized undergo passive reabsorption from the tubular fluid into the surrounding peritubular capillaries. This reabsorption process restricts their elimination through the kidneys. However, the majority of drugs are either weak acids or weak bases, and their ionization level is dependent on pH. By altering the pH of urine, the...
5.6K
ABC Transporters: Exporter01:31

ABC Transporters: Exporter

ATP-binding cassette or ABC transporter is the largest superfamily of integral membrane proteins. The transporters have transmembrane-binding domains (TMDs) and nucleotide-binding domains (NBDs). The TMDs are specific to their substrates, whereas the NBDs are similar to engines that complete ATP hydrolysis to complete the substrate transport. They can be full transporters consisting of two TMDs and NBDs, half transporters with one TMD and NBD, while some encoded with a single TMD or NBD are...
7.2K
Targets for Drug Action: Overview01:26

Targets for Drug Action: Overview

Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
11.4K
Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers01:24

Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers

Adrenergic stimulation generally impacts cardiac rate and rhythm. Specifically, stimulation of the β-adrenoceptors triggers an increase in intracellular calcium ion influx and pacemaker currents, which may cause arrhythmias. Catecholamines like adrenaline also demonstrate β2-adrenoceptor-mediated hypokalemia, impacting cardiac action potential and disrupting the normal cardiac rhythm. Class II antiarrhythmic drugs are β-adrenoceptor antagonists or β-blockers, which...
2.3K