Collateral sensitivity of multidrug-resistant cells to the orphan drug tiopronin

J Med Chem. 2011 Jul 28;54(14):4987-97. doi: 10.1021/jm2001663. Epub 2011 Jun 24.

Abstract

A major challenge in the treatment of cancer is multidrug resistance (MDR) that develops during chemotherapy. Here we demonstrate that tiopronin (1), a thiol-substituted N-propanoylglycine derivative, was selectively toxic to a series of cell lines expressing the drug efflux pump P-glycoprotein (P-gp, ABCB1) and MRP1 (ABCC1). Treatment of MDR cells with 1 led to instability of the ABCB1 mRNA and consequently a reduction in P-gp protein, despite functional assays demonstrating that tiopronin does not interact with P-gp. Long-term exposure of P-gp-expressing cells to 1 sensitized them to doxorubicin and paclitaxel, both P-gp substrates. Treatment of MRP1-overexpressing cells with tiopronin led to a significant reduction in MRP1 protein. Synthesis and screening of analogues of tiopronin demonstrated that the thiol functional group was essential for collateral sensitivity while substitution of the amino acid backbone altered but did not destroy specificity, pointing to future development of targeted analogues.

Publication types

  • Research Support, N.I.H., Intramural
  • Retracted Publication

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Screening Assays, Antitumor
  • HEK293 Cells
  • Humans
  • Multidrug Resistance-Associated Proteins / metabolism
  • Orphan Drug Production
  • Paclitaxel / pharmacology
  • RNA Stability
  • RNA, Messenger / metabolism
  • Structure-Activity Relationship
  • Tiopronin / chemical synthesis
  • Tiopronin / chemistry
  • Tiopronin / pharmacology*

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Multidrug Resistance-Associated Proteins
  • RNA, Messenger
  • Doxorubicin
  • Tiopronin
  • Paclitaxel
  • multidrug resistance-associated protein 1