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Published on: May 15, 2019
A novel delocalized lipophilic cation-chlorambucil conjugate inhibits P-glycoprotein in HepG2/ADM cells
Teng Liu1, Yongbo Peng2, Xiong Li1
1Department of Infectious Diseases and Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha 410008, PR China.
Abstract:
Multidrug resistance (MDR) limits the application of a large number of cancer-fighting agents in clinical therapy. One reason is that P-glycoprotein (Pgp) efflux pumps are usually overexpressed and lead to drug efflux in the cancer cells, which limits the viability of many chemotherapeutics. Current available inhibitors which block the Pgp pump efflux are usually not widely used in clinical practice, because they change other drug pharmacokinetic profiles or increase side effects. Here, through covalent linkage of cancer-targeting delocalized lipophilic cation FF and DNA-damaging drug nitrogen mustard chlorambucil (CLB), we rationally designed and synthesized a tumor-targeting anticancer agent FFCLB. And we found and proved that the FFCLB was capable of reducing the outflow of Pgp substrates efficiently. This conjugate selectively improves adriamycin uptake and toxicity through reducing MDR1 mRNA and Pgp protein expression. Based on molecular targeted strategy, this study can facilitate the discovery of superior MDR reducing agents to provide a more effective and safer way of resensitizing MDR.
Insights
This study introduces FFCLB, a novel anticancer agent that targets tumors and reduces multidrug resistance (MDR) by inhibiting P-glycoprotein (Pgp) efflux pumps. FFCLB enhances chemotherapy effectiveness and safety by improving drug uptake and reducing MDR.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) in cancer is a major challenge, often caused by P-glycoprotein (Pgp) efflux pumps overexpressed in cancer cells.
- Existing Pgp inhibitors have limitations, including adverse pharmacokinetic effects and increased side effects, hindering their clinical use.
Purpose of the Study:
- To design and synthesize a novel tumor-targeting anticancer agent, FFCLB, by covalently linking a cancer-targeting moiety (FF) with a DNA-damaging drug (chlorambucil).
- To evaluate FFCLB's efficacy in reducing Pgp-mediated drug efflux and overcoming MDR.
- To investigate FFCLB's mechanism in reducing MDR1 mRNA and Pgp protein expression.
Main Methods:
- Covalent linkage of delocalized lipophilic cation FF and nitrogen mustard chlorambucil (CLB) to create FFCLB.
- Assessment of FFCLB's ability to reduce Pgp substrate outflow.
- Evaluation of FFCLB's effect on adriamycin uptake and toxicity.
- Analysis of changes in MDR1 mRNA and Pgp protein expression.
Main Results:
- The synthesized FFCLB conjugate effectively reduced the efflux of Pgp substrates.
- FFCLB demonstrated selective enhancement of adriamycin uptake and toxicity in cancer cells.
- The conjugate was found to decrease both MDR1 mRNA and Pgp protein expression.
Conclusions:
- FFCLB is a rationally designed, tumor-targeting anticancer agent with potent MDR-reducing capabilities.
- This molecular targeted strategy offers a promising approach for developing superior MDR-reducing agents.
- FFCLB presents a potential strategy for resensitizing MDR cancers, leading to more effective and safer chemotherapies.
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