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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.

SUBMITTER: Busek P

PROVIDER: S-EPMC9103952 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Busek Petr P Duke-Cohan Jonathan S JS Sedo Aleksi A

Cancers 20220421 9

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 ac ...[more]

PMID: 35565202

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Project description:Background:We had earlier reported that the extract of Pueraria tuberosa significantly inhibits DPP-IV enzyme, resulting in glucose tolerance response in rats. In this study, we have explored the active phytochemicals responsible for this potential. The results have been validated in both fasting and postprandial states in the plasma of normal rats and also in fasting blood and intestinal homogenates of diabetic models. Methods:Pueraria tuberosa water extract (PTWE) was administered to normal Charles Foster rats for 35 days and to diabetic model (65 mg/kg bw) for 10 days. After treatments, oral glucose tolerance test (OGTT) and insulin was done for 90 min, and the changes in the levels of GLP-1, GIP, and DPP-IV activities were monitored in fasting and postprandial states. In the case of the diabetic model, DPP-IV activity was measured in intestinal homogenate and basal insulin in plasma. The components of PTWE were analyzed via HPLC-MS based on their chemical formula, molecular mass, and retention time. Using the molecular docking study, we have selected the top five components having strong binding energy with DPP-IV. Results:The increase in secretion of GLP-1 and GIP was significantly higher in the postprandial state when compared to fasting condition. GLP-1 plasma concentration increased by 5.8 and 2.9 folds and GIP increased by 8.7 and 2.4 folds in PTWE and control rats, respectively. In contrast, the postprandial decrease in DPP-IV specific activities was recorded at 2.3 and 1.4 folds. The response in OGTT and insulin was also consistent with these changes. In comparison to diabetic controls, PTWE-administered rats showed decreased DPP-IV activity in the intestine, leading to enhanced basal insulin concentration. Through molecular docking, we found Puerarone and Robinin to be the most potential phytochemicals of PTWE for DPP-IV inhibition. Binding energy (kcal/mol) and dissociation constant (pM) of Robinin with DPP-IV protein were found to be 7.543 and 2,957,383.75, respectively. For Puerarone, it was 7.376 and 3,920,309, respectively. Conclusions:Thus, this study provides the novel active components that contribute to the DPP-IV inhibitory property of PTWE.

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

Publications

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

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