Does DPP-IV Inhibition Offer New Avenues for Therapeutic Intervention in Malignant Disease?

Abstract

Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis and an attractive therapeutic target. Specific DPP-IV inhibitors (gliptins) are currently used in patients with type 2 diabetes mellitus to promote insulin secretion by prolonging the activity of the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Nevertheless, the modulation of the bioavailability and function of other DPP-IV substrates, including chemokines, raises the possibility that the use of these orally administered drugs with favorable side-effect profiles might be extended beyond the treatment of hyperglycemia. In this review, we critically examine the possible utilization of DPP-IV inhibition in cancer prevention and various aspects of cancer treatment and discuss the potential perils associated with the inhibition of DPP-IV in cancer. The current literature is summarized regarding the possible chemopreventive and cytotoxic effects of gliptins and their potential utility in modulating the anti-tumor immune response, enhancing hematopoietic stem cell transplantation, preventing acute graft-versus-host disease, and alleviating the side-effects of conventional anti-tumor treatments.

Keywords: cancer; chemokine; drug repurposing; gliptin; immune response; stem cells; stromal cell-derived factor; tumor microenvironment.

Figure 1

Potential utility and pitfalls of DPP-IV inhibition by gliptins in anticancer treatment. (1) By preventing DPP-IV-mediated cleavage of chemokines, gliptins may support the recruitment of immune cells with anti-tumor activity into the tumor microenvironment [67,68,157,159]. (2) In addition, changes in cancer cells induced by gliptins may activate macrophages and NK cells [160]. (3) In patients undergoing hematopoietic stem cell transplantation, attenuated cleavage of CXCL12 facilitates the homing and engraftment of donor cells [28,161,162] and result in lower incidence of acute graft-versus-host disease (GvHD) [163]. By reducing the DPP-IV-mediated cleavage of various mediators supporting tissue regeneration, gliptins may increase the resilience of healthy tissues to chemotherapy-induced damage, resulting in (4) accelerated hematopoietic recovery after chemotherapy [164], (5) decreased nephrotoxicity [165,166,167,168,169], cardiotoxicity [170,171], neurotoxicity [172], hepatotoxicity [173], testicular toxicity [174], and reduced mucositis [175]. (6) On the other hand, increased bioavailability of CXCL12 resulting from DPP-IV inhibition, together with gliptin-induced activation of nuclear factor E2–related factor 2 (Nrf2), carries the risk of accelerated epithelial–mesenchymal transition (EMT) and metastatic dissemination of cancer cells [7,8,58,73,80].