Supermolecular drug challenge to overcome drug resistance in cancer cells

Drug Discov Today. 2018 Aug;23(8):1556-1563. doi: 10.1016/j.drudis.2018.05.037. Epub 2018 Jun 4.

Abstract

Overcoming multidrug resistance (MDR) of cancer cells can be accomplished using drug delivery systems in large-molecular-weight ATP-binding cassette transporters before entry into phagolysosomes and by particle-cell-surface interactions. However, these hypotheses do not address the intratumoral heterogeneity in cancer. Anti-MDR must be related to alterations of drug targets, expression of detoxification, as well as altered proliferation. In this study, it is shown that the excellent efficacy and sustainability of anti-MDR is due to a stable ES complex because of the allosteric facilities of artificial enzymes when they are used as supermolecular complexes. The allosteric effect of supermolecular drugs can be explained by the induced-fit model and can provide stable feedback control systems through the loop transfer function of the Hill equation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Allosteric Regulation
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Dextrans / chemistry
  • Drug Carriers
  • Drug Compounding
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Methylmethacrylates / chemistry
  • Mice
  • Models, Biological
  • Molecular Structure
  • Paclitaxel / administration & dosage*
  • Paclitaxel / chemistry
  • Paclitaxel / metabolism
  • Structure-Activity Relationship
  • Tumor Microenvironment

Substances

  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Dextrans
  • Drug Carriers
  • Methylmethacrylates
  • diethylaminoethyl-dextran-methyl methacrylate graft copolymer
  • Paclitaxel