Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers

Arik Dahan, Omri Wolk, Peihua Yang, Sachin Mittal, Zhiqian Wu, Christopher P. Landowski, Gordon L. Amidon

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r2 = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r2 = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI50 = 261 μM) compared to that in SK-MEL-5 cells (GI50 = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting.

Original languageEnglish
Pages (from-to)4385-4394
Number of pages10
JournalMolecular Pharmaceutics
Volume11
Issue number12
DOIs
StatePublished - 1 Dec 2014

Keywords

  • dipeptidyl peptidase IV (DPPIV)
  • drug targeting
  • enzyme-dependent prodrug activation
  • enzyme-targeted delivery
  • selective cytotoxic action

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