A new approach for enhancing differential selectivity of drugs to cancer cells

ACS Chem Biol. 2006 Jun 20;1(5):309-15. doi: 10.1021/cb6001202.


The degree to which anticancer agents selectively target cancer cells is a key determinant in successful therapeutic outcomes. Inhibitors of the Hsp90 molecular chaperone represent an important new class of anticancer agents. We propose here a novel mechanism by which physiochemical properties of Hsp90 inhibitors can be optimized to increase selectivity towards cancer cells. The basis for this approach relies on differential intracellular pH gradients that have been shown to exist between normal and transformed cells. Five Hsp90 inhibitors containing basic or neutral properties were evaluated in antiproliferation assays using cells with variable lysosomal pH. Inhibitors with basic functionalities had reduced activity in cells with normal (low) lysosomal pH but showed significantly greater activity in cells with abnormally elevated lysosomal pH (similar to what has been recorded in many types of cancer cells). Conversely, such selectivity enhancement was not observed for neutral inhibitors. The mechanistic basis for the observed selectivity was demonstrated quantitatively by determining the concentration of inhibitors within relevant intracellular compartments. Collectively, these findings suggest that Hsp90 inhibitors with optimal basicity and physicochemical properties have enhanced selectivity toward cancer cells than their neutral counterparts. It is anticipated that these findings may be applicable to other classes of anticancer agents for improvement of differential selectivity.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor / methods*
  • Drug Screening Assays, Antitumor / trends*
  • HL-60 Cells
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans


  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins