2. Academic Validation
  3. A novel delocalized lipophilic cation-chlorambucil conjugate inhibits P-glycoprotein in HepG2/ADM cells

A novel delocalized lipophilic cation-chlorambucil conjugate inhibits P-glycoprotein in HepG2/ADM cells

  • Bioorg Med Chem. 2017 Oct 15;25(20):5461-5467. doi: 10.1016/j.bmc.2017.08.003.
Teng Liu 1,  Yongbo Peng 2,  Xiong Li 3,  Lian Liu 4,  Fang Liu 4,  Leye He 5
Affiliations

Affiliations

  • 1 Department of Infectious Diseases and Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha 410008, PR China. Electronic address: liutengjy@126.com.
  • 2 Molecular Science and Biomedicine Laboratory, College of Life Sciences, State Key Laboratory for Chemo/Bio-Sensing and Chemometrics, Hunan University, Changsha 410082, PR China.
  • 3 Department of Infectious Diseases and Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha 410008, PR China.
  • 4 School of Stomatology and Medicine, Foshan University, Foshan 528000, PR China.
  • 5 Department of Urology, Third Xiangya Hospital, Central South University, Changsha 410013, PR China.
PMID: 28818459 DOI: 10.1016/j.bmc.2017.08.003
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.

Keywords

Chlorambucil; Delocalized lipophilic cation; Multidrug resistance; P-glycoprotein inhibition; Targeted anticancer.

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