Article
Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers.
Molecular Pharmaceutics
(2014)
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 (r(2) = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r(2) = 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.
Keywords
- dipeptidyl peptidase IV (DPPIV),
- drug targeting,
- enzyme-dependent prodrug activation,
- enzyme-targeted delivery,
- selective cytotoxic action
Disciplines
Publication Date
December, 2014
DOI
https://doi.org/10.1021/mp500483v
Publisher Statement
This is an unofficial adaptation of an article that appeared in an ACS publication. ACS has not endorsed the content of this adaptation or the context of its use.
Citation Information
Arik Dahan, Omri Wolk, Peihua Yang, Sachin Mittal, et al.. "Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers." Molecular Pharmaceutics Vol. 11 Iss. 12 (2014) p. 4385 - 4394 Available at: http://works.bepress.com/zhiqianjames_wu/10/