Dipeptidyl Peptidase IV as a Potential Target for Selective Prodrug Activation and Chemotherapeutic Action in Cancers

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.

Aminopeptidase B can bioconvert L-type amino acid transporter 1 (LAT1)-utilizing amide prodrugs in the brain

“…In addition, dipeptidyl peptidases 1–3 and tripeptidyl peptidase 2, which all may bear a potential as prodrug bioconverting enzymes, were identified from the mouse brain and not in plasma. At least, dipeptidyl peptidase 4 (DPP4, EC 3.4.14.5) has been studied as a selective prodrug-activating enzyme in cancer cells ( Dahan et al, 2014 ). However, the possibility of all the above-mentioned enzymes being the main bioconverting enzyme of the studied prodrugs was ruled out by the fact that this enzyme was cobalt-dependent and activated in elevated pH (8.5), which is optimal only for aminopeptidase B from the listed enzymes in Figure 3 .…”

A highly specific ratiometric two-photon fluorescent probe to detect dipeptidyl peptidase IV in plasma and living systems

“…Besides of being a famous therapeutic target for the treatment of type 2 diabetes, DPP-IV also exhibits costimulatory role in T-cell activation, adhesion to extracellular matrix proteins, and serves as the functional receptor for Middle East respiratory syndrome coronavirus infection (Ohnuma et al, 2008;Raj et al, 2013). Recently, DPP-IV has come back into the centre of attention as a novel molecular marker or a potential therapeutic target for cancer (Cordero et al, 2009;Javidroozi et al, 2012;Dahan et al, 2014;Arrebola et al, 2014;Davies et al, 2015). Furthermore, increasing evidence has demonstrated that the abnormal presence or altered level of DPP-IV in plasma can serve as a potential biomarker for early diagnosis and prognosis evaluation of many diseases, including cholestasis, non-alcoholic fatty liver disease and lung diseases (Perner et al, 1999;Firneisz et al, 2010;Sánchez-Otero et al, 2014).…”

Ratiometric Two-Photon Near-Infrared Probe to Detect DPP IV in Human Plasma, Living Cells, Human Tissues, and Whole Organisms Using Zebrafish

“…Their inhibitors have been introduced to clinics as a class of oral hypoglycemic drugs (called gliptins) that are commonly used to treat type 2 diabetes mellitus and have been demonstrated to efficiently enhance endogenous insulin secretion . DPP IV has previously been associated with the start and progression of several human cancer types; hence, it is considered an important molecular marker and therapeutic target for cancer. , DPP IV is overexpressed in human renal carcinoma tissues, and its blockage reduced several cancer-related processes in the human renal carcinoma cell line Caki-2 . DPP IV has also been shown to be overexpressed in several human colon cancer tissues and in the human Caco-2 colorectal cancer cell line. , In cancerous prostate, the DPP IV activity was enlarged 2-fold versus benign prostatic hyperplasia.…”

“… 20 DPP IV has previously been associated with the start and progression of several human cancer types; hence, it is considered an important molecular marker and therapeutic target for cancer. 21 , 22 DPP IV is overexpressed in human renal carcinoma tissues, and its blockage reduced several cancer-related processes in the human renal carcinoma cell line Caki-2. 23 DPP IV has also been shown to be overexpressed in several human colon cancer tissues and in the human Caco-2 colorectal cancer cell line.…”