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.

Department of Medical Oncology Dana Farber Cancer Institute and Department of Medicine Harvard Medical School Boston MA 02115 USA

Laboratory of Cancer Cell Biology Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University 128 53 Prague Czech Republic

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Murgai M., Giles A., Kaplan R. Physiological, Tumor, and Metastatic Niches: Opportunities and Challenges for Targeting the Tumor Microenvironment. Crit. Rev. Oncog. 2015;20:301–314. doi: 10.1615/CritRevOncog.2015013668. PubMed DOI PMC

Mulvihill E.E., Drucker D.J. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr. Rev. 2014;35:992–1019. doi: 10.1210/er.2014-1035. PubMed DOI PMC

Klemann C., Wagner L., Stephan M., von Horsten S. Cut to the chase: A review of CD26/dipeptidyl peptidase-4’s (DPP4) entanglement in the immune system. Clin. Exp. Immunol. 2016;185:1–21. doi: 10.1111/cei.12781. PubMed DOI PMC

Busek P., Sedo A. Dipeptidyl Peptidase-IV and Related Proteases in Brain Tumors. In: Lichtor T., editor. Evolution of the Molecular Biology of Brain Tumors and the Therapeutic Implications. InTech; London, UK: 2013.

Lambeir A.M., Durinx C., Scharpe S., De Meester I. Dipeptidyl-peptidase IV from bench to bedside: An update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit. Rev. Clin. Lab. Sci. 2003;40:209–294. doi: 10.1080/713609354. PubMed DOI

Mentlein R. Dipeptidyl-peptidase IV (CD26)—Role in the inactivation of regulatory peptides. Regul. Pept. 1999;85:9–24. doi: 10.1016/S0167-0115(99)00089-0. PubMed DOI

Wang H., Liu X., Long M., Huang Y., Zhang L., Zhang R., Zheng Y., Liao X., Wang Y., Liao Q., et al. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis. Sci. Transl. Med. 2016;8:334–351. doi: 10.1126/scitranslmed.aad6095. PubMed DOI

He L., Zhang T., Sun W., Qin Y., Wang Z., Dong W., Zhang H. The DPP-IV inhibitor saxagliptin promotes the migration and invasion of papillary thyroid carcinoma cells via the NRF2/HO1 pathway. Med. Oncol. 2020;37:97. doi: 10.1007/s12032-020-01419-0. PubMed DOI

Durinx C., Lambeir A.M., Bosmans E., Falmagne J.B., Berghmans R., Haemers A., Scharpe S., De Meester I. Molecular characterization of dipeptidyl peptidase activity in serum: Soluble CD26/dipeptidyl peptidase IV is responsible for the release of X-Pro dipeptides. Eur. J. Biochem. 2000;267:5608–5613. doi: 10.1046/j.1432-1327.2000.01634.x. PubMed DOI

Rawlings N.D., Barrett A.J., Bateman A. MEROPS: The database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 2012;40:D343–D350. doi: 10.1093/nar/gkr987. PubMed DOI PMC

Elmansi A.M., Awad M.E., Eisa N.H., Kondrikov D., Hussein K.A., Aguilar-Perez A., Herberg S., Periyasamy-Thandavan S., Fulzele S., Hamrick M.W., et al. What doesn’t kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands. Pharmacol. Ther. 2019;198:90–108. doi: 10.1016/j.pharmthera.2019.02.005. PubMed DOI PMC

Campbell J.E., Drucker D.J. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 2013;17:819–837. doi: 10.1016/j.cmet.2013.04.008. PubMed DOI

American Diabetes Association Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44:S111–S124. doi: 10.2337/dc21-S009. PubMed DOI

Deacon C.F. A review of dipeptidyl peptidase-4 inhibitors. Hot topics from randomized controlled trials. Diabetes Obes. Metab. 2018;20:34–46. doi: 10.1111/dom.13135. PubMed DOI

Kaji K., Yoshiji H., Ikenaka Y., Noguchi R., Aihara Y., Douhara A., Moriya K., Kawaratani H., Shirai Y., Yoshii J., et al. Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats. J. Gastroenterol. 2014;49:481–491. doi: 10.1007/s00535-013-0783-4. PubMed DOI

Tomovic K., Lazarevic J., Kocic G., Deljanin-Ilic M., Anderluh M., Smelcerovic A. Mechanisms and pathways of anti-inflammatory activity of DPP-4 inhibitors in cardiovascular and renal protection. Med. Res. Rev. 2019;39:404–422. doi: 10.1002/med.21513. PubMed DOI

Makdissi A., Ghanim H., Vora M., Green K., Abuaysheh S., Chaudhuri A., Dhindsa S., Dandona P. Sitagliptin exerts an antinflammatory action. J. Clin. Endocrinol. Metab. 2012;97:3333–3341. doi: 10.1210/jc.2012-1544. PubMed DOI PMC

Prakash S., Rai U., Kosuru R., Tiwari V., Singh S. Amelioration of diet-induced metabolic syndrome and fatty liver with sitagliptin via regulation of adipose tissue inflammation and hepatic Adiponectin/AMPK levels in mice. Biochimie. 2020;168:198–209. doi: 10.1016/j.biochi.2019.11.005. PubMed DOI

Lee T.M., Chen W.T., Yang C.C., Lin S.Z., Chang N.C. Sitagliptin attenuates sympathetic innervation via modulating reactive oxygen species and interstitial adenosine in infarcted rat hearts. J. Cell. Mol. Med. 2015;19:418–429. doi: 10.1111/jcmm.12465. PubMed DOI PMC

He Y., Yang G., Yao F., Xian Y., Wang G., Chen L., Lv X., Gao H., Zheng Z., Sun L., et al. Sitagliptin inhibits vascular inflammation via the SIRT6-dependent signaling pathway. Int. Immunopharmacol. 2019;75:105805. doi: 10.1016/j.intimp.2019.105805. PubMed DOI

Kim S.H., Yoo J.H., Lee W.J., Park C.Y. Gemigliptin: An Update of Its Clinical Use in the Management of Type 2 Diabetes Mellitus. Diabetes Metab. J. 2016;40:339–353. doi: 10.4093/dmj.2016.40.5.339. PubMed DOI PMC

Weber A.E., Thornberry N.A. Burger’s Medicinal Chemistry and Drug Discovery. 2021. [(accessed on 20 March 2022)]. Dipeptidyl Peptidase 4 Inhibitors; pp. 1–48. Available online: https://onlinelibrary.wiley.com/doi/book/10.1002/0471266949. DOI

Kim S.H., Jung E., Yoon M.K., Kwon O.H., Hwang D.M., Kim D.W., Kim J., Lee S.M., Yim H.J. Pharmacological profiles of gemigliptin (LC15-0444), a novel dipeptidyl peptidase-4 inhibitor, in vitro and in vivo. Eur. J. Pharmacol. 2016;788:54–64. doi: 10.1016/j.ejphar.2016.06.016. PubMed DOI

Thomas L., Eckhardt M., Langkopf E., Tadayyon M., Himmelsbach F., Mark M. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylm ethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J. Pharmacol. Exp. Ther. 2008;325:175–182. doi: 10.1124/jpet.107.135723. PubMed DOI

Watanabe Y.S., Yasuda Y., Kojima Y., Okada S., Motoyama T., Takahashi R., Oka M. Anagliptin, a potent dipeptidyl peptidase IV inhibitor: Its single-crystal structure and enzyme interactions. J. Enzym. Inhib. Med. Chem. 2015;30:981–988. doi: 10.3109/14756366.2014.1002402. PubMed DOI

Proost P., Struyf S., Schols D., Durinx C., Wuyts A., Lenaerts J.P., De Clercq E., De Meester I., Van Damme J. Processing by CD26/dipeptidyl-peptidase IV reduces the chemotactic and anti-HIV-1 activity of stromal-cell-derived factor-1alpha. FEBS Lett. 1998;432:73–76. doi: 10.1016/S0014-5793(98)00830-8. PubMed DOI

Christopherson K.W., Cooper S., Hangoc G., Broxmeyer H.E. CD26 is essential for normal G-CSF-induced progenitor cell mobilization as determined by CD26(−/−) mice. Exp. Hematol. 2003;31:1126–1134. doi: 10.1016/S0301-472X(03)00256-X. PubMed DOI

Christopherson K.W., 2nd, Hangoc G., Mantel C.R., Broxmeyer H.E. Modulation of hematopoietic stem cell homing and engraftment by CD26. Science. 2004;305:1000–1003. doi: 10.1126/science.1097071. PubMed DOI

Hansen H.H., Gronlund R.V., Baader-Pagler T., Haebel P., Tammen H., Larsen L.K., Jelsing J., Vrang N., Klein T. Characterization of combined linagliptin and Y2R agonist treatment in diet-induced obese mice. Sci. Rep. 2021;11:8060. doi: 10.1038/s41598-021-87539-7. PubMed DOI PMC

Gutheil W.G., Subramanyam M., Flentke G.R., Sanford D.G., Munoz E., Huber B.T., Bachovchin W.W. Human immunodeficiency virus 1 Tat binds to dipeptidyl aminopeptidase IV (CD26): A possible mechanism for Tat’s immunosuppressive activity. Proc. Natl. Acad. Sci. USA. 1994;91:6594–6598. doi: 10.1073/pnas.91.14.6594. PubMed DOI PMC

Blanco J., Valenzuela A., Herrera C., Lluis C., Hovanessian A.G., Franco R. The HIV-1 gp120 inhibits the binding of adenosine deaminase to CD26 by a mechanism modulated by CD4 and CXCR4 expression. FEBS Lett. 2000;477:123–128. doi: 10.1016/S0014-5793(00)01751-8. PubMed DOI

Lu G., Hu Y., Wang Q., Qi J., Gao F., Li Y., Zhang Y., Zhang W., Yuan Y., Bao J., et al. Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature. 2013;500:227–231. doi: 10.1038/nature12328. PubMed DOI PMC

Fox D.A., Hussey R.E., Fitzgerald K.A., Acuto O., Poole C., Palley L., Daley J.F., Schlossman S.F., Reinherz E.L. Ta1, a novel 105 KD human T cell activation antigen defined by a monoclonal antibody. J. Immunol. 1984;133:1250–1256. PubMed

Lepore M., Lewinsohn D.A., Lewinsohn D.M. T cell receptor diversity, specificity and promiscuity of functionally heterogeneous human MR1-restricted T cells. Mol. Immunol. 2021;130:64–68. doi: 10.1016/j.molimm.2020.12.009. PubMed DOI PMC

Waumans Y., Baerts L., Kehoe K., Lambeir A.M., De Meester I. The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis. Front. Immunol. 2015;6:387. doi: 10.3389/fimmu.2015.00387. PubMed DOI PMC

Bengsch B., Seigel B., Flecken T., Wolanski J., Blum H.E., Thimme R. Human Th17 cells express high levels of enzymatically active dipeptidylpeptidase IV (CD26) J. Immunol. 2012;188:5438–5447. doi: 10.4049/jimmunol.1103801. PubMed DOI

Ohnuma K., Yamochi T., Uchiyama M., Nishibashi K., Yoshikawa N., Shimizu N., Iwata S., Tanaka H., Dang N.H., Morimoto C. CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1. Proc. Natl. Acad. Sci. USA. 2004;101:14186–14191. doi: 10.1073/pnas.0405266101. PubMed DOI PMC

Ohnuma K., Uchiyama M., Yamochi T., Nishibashi K., Hosono O., Takahashi N., Kina S., Tanaka H., Lin X., Dang N.H., et al. Caveolin-1 triggers T-cell activation via CD26 in association with CARMA1. J. Biol. Chem. 2007;282:10117–10131. doi: 10.1074/jbc.M609157200. PubMed DOI

Hatano R., Ohnuma K., Yamamoto J., Dang N.H., Morimoto C. CD26-mediated co-stimulation in human CD8(+) T cells provokes effector function via pro-inflammatory cytokine production. Immunology. 2013;138:165–172. doi: 10.1111/imm.12028. PubMed DOI PMC

Huang S., Apasov S., Koshiba M., Sitkovsky M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood. 1997;90:1600–1610. doi: 10.1182/blood.V90.4.1600. PubMed DOI

Kameoka J., Tanaka T., Nojima Y., Schlossman S.F., Morimoto C. Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science. 1993;261:466–469. doi: 10.1126/science.8101391. PubMed DOI

Gines S., Marino M., Mallol J., Canela E.I., Morimoto C., Callebaut C., Hovanessian A., Casado V., Lluis C., Franco R. Regulation of epithelial and lymphocyte cell adhesion by adenosine deaminase-CD26 interaction. Biochem. J. 2002;361:203–209. doi: 10.1042/bj3610203. PubMed DOI PMC

Yu D.M., Slaitini L., Gysbers V., Riekhoff A.G., Kahne T., Knott H.M., De Meester I., Abbott C.A., McCaughan G.W., Gorrell M.D. Soluble CD26/dipeptidyl peptidase IV enhances human lymphocyte proliferation in vitro independent of dipeptidyl peptidase enzyme activity and adenosine deaminase binding. Scand. J. Immunol. 2011;73:102–111. doi: 10.1111/j.1365-3083.2010.02488.x. PubMed DOI

Huhn J., Ehrlich S., Fleischer B., von Bonin A. Molecular analysis of CD26-mediated signal transduction in T cells. Immunol. Lett. 2000;72:127–132. doi: 10.1016/S0165-2478(00)00170-X. PubMed DOI

Metzemaekers M., Van Damme J., Mortier A., Proost P. Regulation of Chemokine Activity—A Focus on the Role of Dipeptidyl Peptidase IV/CD26. Front. Immunol. 2016;7:483. doi: 10.3389/fimmu.2016.00483. PubMed DOI PMC

Zhao X., Zhang K., Daniel P., Wisbrun N., Fuchs H., Fan H. Delayed allogeneic skin graft rejection in CD26-deficient mice. Cell. Mol. Immunol. 2019;16:557–567. doi: 10.1038/s41423-018-0009-z. PubMed DOI PMC

Klemann C., Schade J., Pabst R., Leitner S., Stiller J., von Horsten S., Stephan M. CD26/dipeptidyl peptidase 4-deficiency alters thymic emigration patterns and leukcocyte subsets in F344-rats age-dependently. Clin. Exp. Immunol. 2009;155:357–365. doi: 10.1111/j.1365-2249.2008.03839.x. PubMed DOI PMC

Vora K.A., Porter G., Peng R., Cui Y., Pryor K., Eiermann G., Zaller D.M. Genetic ablation or pharmacological blockade of dipeptidyl peptidase IV does not impact T cell-dependent immune responses. BMC Immunol. 2009;10:19. doi: 10.1186/1471-2172-10-19. PubMed DOI PMC

Reinhold D., Goihl A., Wrenger S., Reinhold A., Kuhlmann U.C., Faust J., Neubert K., Thielitz A., Brocke S., Tager M., et al. Role of dipeptidyl peptidase IV (DP IV)-like enzymes in T lymphocyte activation: Investigations in DP IV/CD26-knockout mice. Clin. Chem. Lab. Med. 2009;47:268–274. doi: 10.1515/CCLM.2009.062. PubMed DOI

The Immunological Genome Project ImmGen at 15. Nat. Immunol. 2020;21:700–703. doi: 10.1038/s41590-020-0687-4. PubMed DOI

Cheng H.C., Abdel-Ghany M., Pauli B.U. A novel consensus motif in fibronectin mediates dipeptidyl peptidase IV adhesion and metastasis. J. Biol. Chem. 2003;278:24600–24607. doi: 10.1074/jbc.M303424200. PubMed DOI

Sedo A., Stremenova J., Busek P., Duke-Cohan J.S. Dipeptidyl peptidase-IV and related molecules: Markers of malignancy? Expert Opin. Med. Diagn. 2008;2:677–689. doi: 10.1517/17530059.2.6.677. PubMed DOI

Enz N., Vliegen G., De Meester I., Jungraithmayr W. CD26/DPP4—A potential biomarker and target for cancer therapy. Pharmacol. Ther. 2019;198:135–159. doi: 10.1016/j.pharmthera.2019.02.015. PubMed DOI

Beckenkamp A., Davies S., Willig J.B., Buffon A. DPPIV/CD26: A tumor suppressor or a marker of malignancy? Tumour Biol. 2016;37:7059–7073. doi: 10.1007/s13277-016-5005-2. PubMed DOI

Wesley U.V., Tiwari S., Houghton A.N. Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells. Int. J. Cancer. 2004;109:855–866. doi: 10.1002/ijc.20091. PubMed DOI

Arscott W.T., LaBauve A.E., May V., Wesley U.V. Suppression of neuroblastoma growth by dipeptidyl peptidase IV: Relevance of chemokine regulation and caspase activation. Oncogene. 2009;28:479–491. doi: 10.1038/onc.2008.402. PubMed DOI PMC

Wesley U.V., Albino A.P., Tiwari S., Houghton A.N. A role for dipeptidyl peptidase IV in suppressing the malignant phenotype of melanocytic cells. J. Exp. Med. 1999;190:311–322. doi: 10.1084/jem.190.3.311. PubMed DOI PMC

Narducci M.G., Scala E., Bresin A., Caprini E., Picchio M.C., Remotti D., Ragone G., Nasorri F., Frontani M., Arcelli D., et al. Skin homing of Sezary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV. Blood. 2006;107:1108–1115. doi: 10.1182/blood-2005-04-1492. PubMed DOI

Angevin E., Isambert N., Trillet-Lenoir V., You B., Alexandre J., Zalcman G., Vielh P., Farace F., Valleix F., Podoll T., et al. First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers. Br. J. Cancer. 2017;116:1126–1134. doi: 10.1038/bjc.2017.62. PubMed DOI PMC

Lee J.J., Wang T.Y., Liu C.L., Chien M.N., Chen M.J., Hsu Y.C., Leung C.H., Cheng S.P. Dipeptidyl Peptidase IV as a Prognostic Marker and Therapeutic Target in Papillary Thyroid Carcinoma. J. Clin. Endocrinol. Metab. 2017;102:2930–2940. doi: 10.1210/jc.2017-00346. PubMed DOI

Jiang Y.X., Yang S.W., Li P.A., Luo X., Li Z.Y., Hao Y.X., Yu P.W. The promotion of the transformation of quiescent gastric cancer stem cells by IL-17 and the underlying mechanisms. Oncogene. 2017;36:1256–1264. doi: 10.1038/onc.2016.291. PubMed DOI PMC

Larrinaga G., Perez I., Sanz B., Beitia M., Errarte P., Fernandez A., Blanco L., Etxezarraga M.C., Gil J., Lopez J.I. Dipeptidyl-peptidase IV activity is correlated with colorectal cancer prognosis. PLoS ONE. 2015;10:e0119436. doi: 10.1371/journal.pone.0119436. PubMed DOI PMC

Pang R., Law W.L., Chu A.C., Poon J.T., Lam C.S., Chow A.K., Ng L., Cheung L.W., Lan X.R., Lan H.Y., et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. 2010;6:603–615. doi: 10.1016/j.stem.2010.04.001. PubMed DOI

Jang J.H., Baerts L., Waumans Y., De Meester I., Yamada Y., Limani P., Gil-Bazo I., Weder W., Jungraithmayr W. Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice. Clin. Exp. Metastasis. 2015;32:677–687. doi: 10.1007/s10585-015-9736-z. PubMed DOI

Goscinski M.A., Suo Z.H., Nesland J.M., Florenes V.A., Giercksky K.E. Dipeptidyl peptidase IV expression in cancer and stromal cells of human esophageal squamous cell carcinomas, adenocarcinomas and squamous cell carcinoma cell lines. APMIS. 2008;116:823–831. doi: 10.1111/j.1600-0463.2008.01029.x. PubMed DOI

Dietrich P., Wormser L., Fritz V., Seitz T., De Maria M., Schambony A., Kremer A.E., Gunther C., Itzel T., Thasler W.E., et al. Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer. J. Clin. Investig. 2020;130:2509–2526. doi: 10.1172/JCI131919. PubMed DOI PMC

Hollande C., Boussier J., Ziai J., Nozawa T., Bondet V., Phung W., Lu B., Duffy D., Paradis V., Mallet V., et al. Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth. Nat. Immunol. 2019;20:257–264. doi: 10.1038/s41590-019-0321-5. PubMed DOI

Nishina S., Yamauchi A., Kawaguchi T., Kaku K., Goto M., Sasaki K., Hara Y., Tomiyama Y., Kuribayashi F., Torimura T., et al. Dipeptidyl Peptidase 4 Inhibitors Reduce Hepatocellular Carcinoma by Activating Lymphocyte Chemotaxis in Mice. Cell. Mol. Gastroenterol. Hepatol. 2019;7:115–134. doi: 10.1016/j.jcmgh.2018.08.008. PubMed DOI PMC

Henderson J.M., Xiang M.S.W., Huang J.C., Wetzel S., Jiang L., Lai J.H., Wu W., Kench J.G., Bachovchin W.W., Roediger B., et al. Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma. Cancers. 2021;13:5495. doi: 10.3390/cancers13215495. PubMed DOI PMC

Wilson M.J., Ruhland A.R., Quast B.J., Reddy P.K., Ewing S.L., Sinha A.A. Dipeptidylpeptidase IV activities are elevated in prostate cancers and adjacent benign hyperplastic glands. J. Androl. 2000;21:220–226. PubMed

Lu Z., Qi L., Bo X.J., Liu G.D., Wang J.M., Li G. Expression of CD26 and CXCR4 in prostate carcinoma and its relationship with clinical parameters. J. Res. Med. Sci. 2013;18:647–652. PubMed PMC

Wesley U.V., McGroarty M., Homoyouni A. Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. Cancer Res. 2005;65:1325–1334. doi: 10.1158/0008-5472.CAN-04-1852. PubMed DOI

Sun Y.X., Pedersen E.A., Shiozawa Y., Havens A.M., Jung Y., Wang J., Pienta K.J., Taichman R.S. CD26/dipeptidyl peptidase IV regulates prostate cancer metastasis by degrading SDF-1/CXCL12. Clin. Exp. Metastasis. 2008;25:765–776. doi: 10.1007/s10585-008-9188-9. PubMed DOI

Russo J.W., Gao C., Bhasin S.S., Voznesensky O.S., Calagua C., Arai S., Nelson P.S., Montgomery B., Mostaghel E.A., Corey E., et al. Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer. Cancer Res. 2018;78:6354–6362. doi: 10.1158/0008-5472.CAN-18-0687. PubMed DOI PMC

Stremenova J., Krepela E., Mares V., Trim J., Dbaly V., Marek J., Vanickova Z., Lisa V., Yea C., Sedo A. Expression and enzymatic activity of dipeptidyl peptidase-IV in human astrocytic tumours are associated with tumour grade. Int. J. Oncol. 2007;31:785–792. doi: 10.3892/ijo.31.4.785. PubMed DOI

Busek P., Stremenova J., Krepela E., Sedo A. Modulation of substance P signaling by dipeptidyl peptidase-IV enzymatic activity in human glioma cell lines. Physiol. Res. 2008;57:443–449. doi: 10.33549/physiolres.931231. PubMed DOI

Busek P., Stremenova J., Sromova L., Hilser M., Balaziova E., Kosek D., Trylcova J., Strnad H., Krepela E., Sedo A. Dipeptidyl peptidase-IV inhibits glioma cell growth independent of its enzymatic activity. Int. J. Biochem. Cell Biol. 2012;44:738–747. doi: 10.1016/j.biocel.2012.01.011. PubMed DOI

Choi H.J., Kim J.Y., Lim S.C., Kim G., Yun H.J., Choi H.S. Dipeptidyl peptidase 4 promotes epithelial cell transformation and breast tumourigenesis via induction of PIN1 gene expression. Br. J. Pharmacol. 2015;172:5096–5109. doi: 10.1111/bph.13274. PubMed DOI PMC

Leccia F., Nardone A., Corvigno S., Vecchio L.D., De Placido S., Salvatore F., Veneziani B.M. Cytometric and biochemical characterization of human breast cancer cells reveals heterogeneous myoepithelial phenotypes. Cytom. A. 2012;81:960–972. doi: 10.1002/cyto.a.22095. PubMed DOI

Yang F., Takagaki Y., Yoshitomi Y., Ikeda T., Li J., Kitada M., Kumagai A., Kawakita E., Shi S., Kanasaki K., et al. Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial-Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis. Cancer Res. 2019;79:735–746. doi: 10.1158/0008-5472.CAN-18-0620. PubMed DOI

Li S., Fan Y., Kumagai A., Kawakita E., Kitada M., Kanasaki K., Koya D. Deficiency in Dipeptidyl Peptidase-4 Promotes Chemoresistance through the CXCL12/CXCR4/mTOR/TGFbeta Signaling Pathway in Breast Cancer Cells. Int. J. Mol. Sci. 2020;21:805. doi: 10.3390/ijms21030805. PubMed DOI PMC

Yang X., Zhang X., Wu R., Huang Q., Jiang Y., Qin J., Yao F., Jin G., Zhang Y. DPPIV promotes endometrial carcinoma cell proliferation, invasion and tumorigenesis. Oncotarget. 2017;8:8679–8692. doi: 10.18632/oncotarget.14412. PubMed DOI PMC

Khin E.E., Kikkawa F., Ino K., Kajiyama H., Suzuki T., Shibata K., Tamakoshi K., Nagasaka T., Mizutani S. Dipeptidyl peptidase IV expression in endometrial endometrioid adenocarcinoma and its inverse correlation with tumor grade. Am. J. Obstet. Gynecol. 2003;188:670–676. doi: 10.1067/mob.2003.169. PubMed DOI

Kikkawa F., Kajiyama H., Shibata K., Ino K., Nomura S., Mizutani S. Dipeptidyl peptidase IV in tumor progression. Biochim. Biophys. Acta. 2005;1751:45–51. doi: 10.1016/j.bbapap.2004.09.028. PubMed DOI

Kajiyama H., Kikkawa F., Khin E., Shibata K., Ino K., Mizutani S. Dipeptidyl peptidase IV overexpression induces up-regulation of E-cadherin and tissue inhibitors of matrix metalloproteinases, resulting in decreased invasive potential in ovarian carcinoma cells. Cancer Res. 2003;63:2278–2283. PubMed

Kajiyama H., Shibata K., Ino K., Mizutani S., Nawa A., Kikkawa F. The expression of dipeptidyl peptidase IV (DPPIV/CD26) is associated with enhanced chemosensitivity to paclitaxel in epithelial ovarian carcinoma cells. Cancer Sci. 2010;101:347–354. doi: 10.1111/j.1349-7006.2009.01378.x. PubMed DOI PMC

Zhang M., Xu L., Wang X., Sun B., Ding J. Expression levels of seprase/FAPalpha and DPPIV/CD26 in epithelial ovarian carcinoma. Oncol. Lett. 2015;10:34–42. doi: 10.3892/ol.2015.3151. PubMed DOI PMC

Busek P., Vanickova Z., Hrabal P., Brabec M., Fric P., Zavoral M., Skrha J., Kmochova K., Laclav M., Bunganic B., et al. Increased tissue and circulating levels of dipeptidyl peptidase-IV enzymatic activity in patients with pancreatic ductal adenocarcinoma. Pancreatology. 2016;16:829–838. doi: 10.1016/j.pan.2016.06.001. PubMed DOI

Matveyenko A.V., Dry S., Cox H.I., Moshtaghian A., Gurlo T., Galasso R., Butler A.E., Butler P.C. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: Interactions with metformin. Diabetes. 2009;58:1604–1615. doi: 10.2337/db09-0058. PubMed DOI PMC

Butler A.E., Campbell-Thompson M., Gurlo T., Dawson D.W., Atkinson M., Butler P.C. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013;62:2595–2604. doi: 10.2337/db12-1686. PubMed DOI PMC

Ueberberg S., Jutte H., Uhl W., Schmidt W., Nauck M., Montanya E., Tannapfel A., Meier J. Histological changes in endocrine and exocrine pancreatic tissue from patients exposed to incretin-based therapies. Diabetes Obes. Metab. 2016;18:1253–1262. doi: 10.1111/dom.12766. PubMed DOI

Aston-Mourney K., Subramanian S.L., Zraika S., Samarasekera T., Meier D.T., Goldstein L.C., Hull R.L. One year of sitagliptin treatment protects against islet amyloid-associated beta-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice. Am. J. Physiol. Endocrinol. Metab. 2013;305:E475–E484. doi: 10.1152/ajpendo.00025.2013. PubMed DOI PMC

Cox A.R., Lam C.J., Rankin M.M., Rios J.S., Chavez J., Bonnyman C.W., King K.B., Wells R.A., Anthony D., Tu J.X., et al. Incretin Therapies Do Not Expand beta-Cell Mass or Alter Pancreatic Histology in Young Male Mice. Endocrinology. 2017;158:1701–1714. doi: 10.1210/en.2017-00027. PubMed DOI PMC

Busch S.J., Hoffmann P., Sahota P., Johnson R., Kothny W., Meyer F., Foley J.E. Studies in rodents with the dipeptidyl peptidase-4 inhibitor vildagliptin to evaluate possible drug-induced pancreatic histological changes that are predictive of pancreatitis and cancer development in man. Diabetes Obes. Metab. 2013;15:72–76. doi: 10.1111/j.1463-1326.2012.01678.x. PubMed DOI

Pinto L.C., Rados D.V., Barkan S.S., Leitao C.B., Gross J.L. Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: A meta-analysis with trial sequential analysis. Sci. Rep. 2018;8:782. doi: 10.1038/s41598-017-19055-6. PubMed DOI PMC

Abd El Aziz M., Cahyadi O., Meier J.J., Schmidt W.E., Nauck M.A. Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: A meta-analysis based on cardiovascular outcomes trials. Diabetes Obes. Metab. 2020;22:699–704. doi: 10.1111/dom.13924. PubMed DOI

Dicembrini I., Montereggi C., Nreu B., Mannucci E., Monami M. Pancreatitis and pancreatic cancer in patientes treated with Dipeptidyl Peptidase-4 inhibitors: An extensive and updated meta-analysis of randomized controlled trials. Diabetes Res. Clin. Pract. 2020;159:107981. doi: 10.1016/j.diabres.2019.107981. PubMed DOI

Dicembrini I., Nreu B., Montereggi C., Mannucci E., Monami M. Risk of cancer in patients treated with dipeptidyl peptidase-4 inhibitors: An extensive meta-analysis of randomized controlled trials. Acta Diabetol. 2020;57:689–696. doi: 10.1007/s00592-020-01479-8. PubMed DOI

Lee D.Y., Yu J.H., Park S., Han K., Kim N.H., Yoo H.J., Choi K.M., Baik S.H., Kim N.H., Seo J.A. The influence of diabetes and antidiabetic medications on the risk of pancreatic cancer: A nationwide population-based study in Korea. Sci. Rep. 2018;8:9719. doi: 10.1038/s41598-018-27965-2. PubMed DOI PMC

Boniol M., Franchi M., Bota M., Leclercq A., Guillaume J., van Damme N., Corrao G., Autier P., Boyle P. Incretin-Based Therapies and the Short-term Risk of Pancreatic Cancer: Results From Two Retrospective Cohort Studies. Diabetes Care. 2018;41:286–292. doi: 10.2337/dc17-0280. PubMed DOI

Lee M., Sun J., Han M., Cho Y., Lee J.Y., Nam C.M., Kang E.S. Nationwide Trends in Pancreatitis and Pancreatic Cancer Risk Among Patients With Newly Diagnosed Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors. Diabetes Care. 2019;42:2057–2064. doi: 10.2337/dc18-2195. PubMed DOI

Abrahami D., Douros A., Yin H., Yu O.H., Faillie J.L., Montastruc F., Platt R.W., Bouganim N., Azoulay L. Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: Population based cohort study. BMJ. 2018;363:k4880. doi: 10.1136/bmj.k4880. PubMed DOI PMC

Pech V., Abusaada K., Alemany C. Dipeptidyl Peptidase-4 Inhibition May Stimulate Progression of Carcinoid Tumor. Case Rep. Endocrinol. 2015;2015:952019. doi: 10.1155/2015/952019. PubMed DOI PMC

Kim K.R., Rhee S.D., Kim H.Y., Jung W.H., Yang S.D., Kim S.S., Ahn J.H., Cheon H.G. KR-62436, 6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitr ile, is a novel dipeptidyl peptidase-IV (DPP-IV) inhibitor with anti-hyperglycemic activity. Eur. J. Pharmacol. 2005;518:63–70. doi: 10.1016/j.ejphar.2005.05.030. PubMed DOI

Rathmann W., Kostev K. Association of dipeptidyl peptidase 4 inhibitors with risk of metastases in patients with type 2 diabetes and breast, prostate or digestive system cancer. J. Diabetes Complicat. 2017;31:687–692. doi: 10.1016/j.jdiacomp.2017.01.012. PubMed DOI

Noh Y., Jeon S.M., Shin S. Association between glucose-lowering treatment and cancer metastasis among patients with preexisting type 2 diabetes and incident malignancy. Int. J. Cancer. 2019;144:1530–1539. doi: 10.1002/ijc.31870. PubMed DOI

Tseng C.H. Sitagliptin May Reduce Breast Cancer Risk in Women With Type 2 Diabetes. Clin. Breast Cancer. 2017;17:211–218. doi: 10.1016/j.clbc.2016.11.002. PubMed DOI

Tseng C.H. Sitagliptin may reduce prostate cancer risk in male patients with type 2 diabetes. Oncotarget. 2017;8:19057–19064. doi: 10.18632/oncotarget.12137. PubMed DOI PMC

Hsu W.H., Sue S.P., Liang H.L., Tseng C.W., Lin H.C., Wen W.L., Lee M.Y. Dipeptidyl Peptidase 4 Inhibitors Decrease the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis C Infection and Type 2 Diabetes Mellitus: A Nationwide Study in Taiwan. Front. Public Health. 2021;9:711723. doi: 10.3389/fpubh.2021.711723. PubMed DOI PMC

Kamada S., Namekawa T., Ikeda K., Suzuki T., Kagawa M., Takeshita H., Yano A., Okamoto K., Ichikawa T., Horie-Inoue K., et al. Functional inhibition of cancer stemness-related protein DPP4 rescues tyrosine kinase inhibitor resistance in renal cell carcinoma. Oncogene. 2021;40:3899–3913. doi: 10.1038/s41388-021-01822-5. PubMed DOI

Stecca B.A., Nardo B., Chieco P., Mazziotti A., Bolondi L., Cavallari A. Aberrant dipeptidyl peptidase IV (DPP IV/CD26) expression in human hepatocellular carcinoma. J. Hepatol. 1997;27:337–345. doi: 10.1016/S0168-8278(97)80180-8. PubMed DOI

Qin C.J., Zhao L.H., Zhou X., Zhang H.L., Wen W., Tang L., Zeng M., Wang M.D., Fu G.B., Huang S., et al. Inhibition of dipeptidyl peptidase IV prevents high fat diet-induced liver cancer angiogenesis by downregulating chemokine ligand 2. Cancer Lett. 2018;420:26–37. doi: 10.1016/j.canlet.2018.01.064. PubMed DOI

Khalil R., Shata A., Abd El-Kader E.M., Sharaf H., Abdo W.S., Amin N.A., Saber S. Vildagliptin, a DPP-4 inhibitor, attenuates carbon tetrachloride-induced liver fibrosis by targeting ERK1/2, p38alpha, and NF-kappaB signaling. Toxicol. Appl. Pharmacol. 2020;407:115246. doi: 10.1016/j.taap.2020.115246. PubMed DOI

Abd Elmaaboud M., Khattab H., Shalaby S. Hepatoprotective effect of linagliptin against liver fibrosis induced by carbon tetrachloride in mice. Can. J. Physiol. Pharmacol. 2021;99:294–302. doi: 10.1139/cjpp-2020-0049. PubMed DOI

Sokar S.S., El-Sayad M.E., Ghoneim M.E., Shebl A.M. Combination of Sitagliptin and Silymarin ameliorates liver fibrosis induced by carbon tetrachloride in rats. Biomed. Pharmacother. 2017;89:98–107. doi: 10.1016/j.biopha.2017.02.010. PubMed DOI

Wang X.M., Holz L.E., Chowdhury S., Cordoba S.P., Evans K.A., Gall M.G., de Ribeiro A.J.V., Zheng Y.Z., Levy M.T., Yu D.M., et al. The pro-fibrotic role of dipeptidyl peptidase 4 in carbon tetrachloride-induced experimental liver injury. Immunol. Cell Biol. 2017;95:443–453. doi: 10.1038/icb.2016.116. PubMed DOI

Abd Elhameed A.G., Helal M.G., Said E., Salem H.A. Saxagliptin defers thioacetamide-induced hepatocarcinogenesis in rats: A novel suppressive impact on Wnt/Hedgehog/Notch1 signaling. Environ. Toxicol. Pharmacol. 2021;86:103668. doi: 10.1016/j.etap.2021.103668. PubMed DOI

Baumeier C., Schluter L., Saussenthaler S., Laeger T., Rodiger M., Alaze S.A., Fritsche L., Haring H.U., Stefan N., Fritsche A., et al. Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease. Mol. Metab. 2017;6:1254–1263. doi: 10.1016/j.molmet.2017.07.016. PubMed DOI PMC

Kawakubo M., Tanaka M., Ochi K., Watanabe A., Saka-Tanaka M., Kanamori Y., Yoshioka N., Yamashita S., Goto M., Itoh M., et al. Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects. Sci. Rep. 2020;10:983. doi: 10.1038/s41598-020-57935-6. PubMed DOI PMC

Kawaguchi T., Nakano D., Koga H., Torimura T. Effects of a DPP4 Inhibitor on Progression of NASH-related HCC and the p62/Keap1/Nrf2-Pentose Phosphate Pathway in a Mouse Model. Liver Cancer. 2019;8:359–372. doi: 10.1159/000491763. PubMed DOI PMC

Ozutsumi T., Namisaki T., Shimozato N., Kaji K., Tsuji Y., Kaya D., Fujinaga Y., Furukawa M., Nakanishi K., Sato S., et al. Combined Treatment with Sodium-Glucose Cotransporter-2 Inhibitor (Canagliflozin) and Dipeptidyl Peptidase-4 Inhibitor (Teneligliptin) Alleviates NASH Progression in A Non-Diabetic Rat Model of Steatohepatitis. Int. J. Mol. Sci. 2020;21:2164. doi: 10.3390/ijms21062164. PubMed DOI PMC

Okura Y., Namisaki T., Moriya K., Kitade M., Takeda K., Kaji K., Noguchi R., Nishimura N., Seki K., Kawaratani H., et al. Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis. Hepatol. Res. Off. J. Jpn. Soc. Hepatol. 2017;47:1317–1328. doi: 10.1111/hepr.12860. PubMed DOI

Billeschou A., Hunt J.E., Ghimire A., Holst J.J., Kissow H. Intestinal Adaptation upon Chemotherapy-Induced Intestinal Injury in Mice Depends on GLP-2 Receptor Activation. Biomedicines. 2021;9:46. doi: 10.3390/biomedicines9010046. PubMed DOI PMC

Masur K., Schwartz F., Entschladen F., Niggemann B., Zaenker K.S. DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regul. Pept. 2006;137:147–155. doi: 10.1016/j.regpep.2006.07.003. PubMed DOI

Abrahami D., Yin H., Yu O.H.Y., Pollak M.N., Azoulay L. Incretin-based Drugs and the Incidence of Colorectal Cancer in Patients with Type 2 Diabetes. Epidemiology. 2018;29:246–253. doi: 10.1097/EDE.0000000000000793. PubMed DOI

Ng L., Foo D.C., Wong C.K., Man A.T., Lo O.S., Law W.L. Repurposing DPP-4 Inhibitors for Colorectal Cancer: A Retrospective and Single Center Study. Cancers. 2021;13:3588. doi: 10.3390/cancers13143588. PubMed DOI PMC

Ali A., Fuentes A., Skelton W.I., Wang Y., McGorray S., Shah C., Bishnoi R., Dang L.H., Dang N.H. A multi-center retrospective analysis of the effect of DPP4 inhibitors on progression-free survival in advanced airway and colorectal cancers. Mol. Clin. Oncol. 2019;10:118–124. doi: 10.3892/mco.2018.1766. PubMed DOI PMC

Bishnoi R., Hong Y.R., Shah C., Ali A., Skelton W.P.t., Huo J., Dang N.H., Dang L.H. Dipeptidyl peptidase 4 inhibitors as novel agents in improving survival in diabetic patients with colorectal cancer and lung cancer: A Surveillance Epidemiology and Endpoint Research Medicare study. Cancer Med. 2019;8:3918–3927. doi: 10.1002/cam4.2278. PubMed DOI PMC

Femia A.P., Raimondi L., Maglieri G., Lodovici M., Mannucci E., Caderni G. Long-term treatment with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, reduces colon carcinogenesis and reactive oxygen species in 1,2-dimethylhydrazine-induced rats. Int. J. Cancer. 2013;133:2498–2503. doi: 10.1002/ijc.28260. PubMed DOI

Yorifuji N., Inoue T., Iguchi M., Fujiwara K., Kakimoto K., Nouda S., Okada T., Kawakami K., Abe Y., Takeuchi T., et al. The dipeptidyl peptidase-4 inhibitor sitagliptin suppresses mouse colon tumorigenesis in type 2 diabetic mice. Oncol. Rep. 2016;35:676–682. doi: 10.3892/or.2015.4429. PubMed DOI

Fujiwara K., Inoue T., Henmi Y., Hirata Y., Naka Y., Hara A., Kakimoto K., Nouda S., Okada T., Kawakami K., et al. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, suppresses CXCL5 and SDF-1 and does not accelerate intestinal neoplasia formation in Apc(Min/+) mice fed a high-fat diet. Oncol. Lett. 2017;14:4355–4360. doi: 10.3892/ol.2017.6698. PubMed DOI PMC

Kabel A.M., Atef A., Estfanous R.S. Ameliorative potential of sitagliptin and/or resveratrol on experimentally-induced clear cell renal cell carcinoma. Biomed. Pharmacother. 2018;97:667–674. doi: 10.1016/j.biopha.2017.10.149. PubMed DOI

Arwert E.N., Mentink R.A., Driskell R.R., Hoste E., Goldie S.J., Quist S., Watt F.M. Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation. Oncogene. 2012;31:992–1000. doi: 10.1038/onc.2011.298. PubMed DOI

Zhao M., Chen J., Yuan Y., Zou Z., Lai X., Rahmani D.M., Wang F., Xi Y., Huang Q., Bu S. Dipeptidyl peptidase-4 inhibitors and cancer risk in patients with type 2 diabetes: A meta-analysis of randomized clinical trials. Sci. Rep. 2017;7:8273. doi: 10.1038/s41598-017-07921-2. PubMed DOI PMC

Shirakawa J., Terauchi Y. Potential linkage between dipeptidyl peptidase-4 inhibitor use and the risk of pancreatitis/pancreatic cancer. J. Diabetes Investig. 2020;11:789–791. doi: 10.1111/jdi.13192. PubMed DOI PMC

Overbeek J.A., Bakker M., van der Heijden A., van Herk-Sukel M.P.P., Herings R.M.C., Nijpels G. Risk of dipeptidyl peptidase-4 (DPP-4) inhibitors on site-specific cancer: A systematic review and meta-analysis. Diabetes Metab. Res. Rev. 2018;34:e3004. doi: 10.1002/dmrr.3004. PubMed DOI

Choi Y.J., Kim D.J., Shin S. Incident cancer risk in dipeptidyl peptidase-4 inhibitor-treated patients with type 2 diabetes mellitus. Cancer Manag. Res. 2019;11:7427–7438. doi: 10.2147/CMAR.S215107. PubMed DOI PMC

Kim S.H., Kang J.G., Kim C.S., Ihm S.H., Choi M.G., Yoo H.J., Lee S.J. Synergistic cytotoxicity of the dipeptidyl peptidase-IV inhibitor gemigliptin with metformin in thyroid carcinoma cells. Endocrine. 2018;59:383–394. doi: 10.1007/s12020-017-1503-2. PubMed DOI

Kim S.H., Kang J.G., Kim C.S., Ihm S.H., Choi M.G., Yoo H.J., Lee S.J. Gemigliptin, a novel dipeptidyl peptidase-IV inhibitor, exerts a synergistic cytotoxicity with the histone deacetylase inhibitor PXD101 in thyroid carcinoma cells. J. Endocrinol. Investig. 2018;41:677–689. doi: 10.1007/s40618-017-0792-x. PubMed DOI

Kim S.H., Kang J.G., Kim C.S., Ihm S.H., Choi M.G., Yoo H.J., Lee S.J. The dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with NVP-AUY922 has a cytotoxic activity in thyroid carcinoma cells. Tumour Biol. 2017;39:1010428317722068. doi: 10.1177/1010428317722068. PubMed DOI

Wang Q., Lu P., Wang T., Zheng Q., Li Y., Leng S.X., Meng X., Wang B., Xie J., Zhang H. Sitagliptin affects gastric cancer cells proliferation by suppressing Melanoma-associated antigen-A3 expression through Yes-associated protein inactivation. Cancer Med. 2020;9:3816–3828. doi: 10.1002/cam4.3024. PubMed DOI PMC

Varela-Calvino R., Rodriguez-Quiroga M., Carvalho P.D., Martins F., Serra-Roma A., Vazquez-Iglesias L., de la Cadena M.P., Velho S., Cordero O.J. The mechanism of sitagliptin inhibition of colorectal cancer cell lines’ metastatic functionalities. IUBMB Life. 2021;73:761–773. doi: 10.1002/iub.2454. PubMed DOI

Sliwinska A., Rogalska A., Marczak A., Kasznicki J., Drzewoski J. Metformin, but not sitagliptin, enhances WP 631-induced apoptotic HepG2 cell death. Toxicol. Vitr. 2015;29:1116–1123. doi: 10.1016/j.tiv.2015.04.019. PubMed DOI

Beckenkamp A., Willig J.B., Santana D.B., Nascimento J., Paccez J.D., Zerbini L.F., Bruno A.N., Pilger D.A., Wink M.R., Buffon A. Differential Expression and Enzymatic Activity of DPPIV/CD26 Affects Migration Ability of Cervical Carcinoma Cells. PLoS ONE. 2015;10:e0134305. doi: 10.1371/journal.pone.0134305. PubMed DOI PMC

Spagnuolo P.A., Hurren R., Gronda M., MacLean N., Datti A., Basheer A., Lin F.H., Wang X., Wrana J., Schimmer A.D. Inhibition of intracellular dipeptidyl peptidases 8 and 9 enhances parthenolide’s anti-leukemic activity. Leukemia. 2013;27:1236–1244. doi: 10.1038/leu.2013.9. PubMed DOI

Sato T., Tatekoshi A., Takada K., Iyama S., Kamihara Y., Jawaid P., Rehman M.U., Noguchi K., Kondo T., Kajikawa S., et al. DPP8 is a novel therapeutic target for multiple myeloma. Sci. Rep. 2019;9:18094. doi: 10.1038/s41598-019-54695-w. PubMed DOI PMC

Herrmann H., Sadovnik I., Cerny-Reiterer S., Rulicke T., Stefanzl G., Willmann M., Hoermann G., Bilban M., Blatt K., Herndlhofer S., et al. Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood. 2014;123:3951–3962. doi: 10.1182/blood-2013-10-536078. PubMed DOI

Willmann M., Sadovnik I., Eisenwort G., Entner M., Bernthaler T., Stefanzl G., Hadzijusufovic E., Berger D., Herrmann H., Hoermann G., et al. Evaluation of cooperative antileukemic effects of nilotinib and vildagliptin in Ph(+) chronic myeloid leukemia. Exp. Hematol. 2018;57:50–59.e56. doi: 10.1016/j.exphem.2017.09.012. PubMed DOI PMC

Bergman A.J., Stevens C., Zhou Y., Yi B., Laethem M., De Smet M., Snyder K., Hilliard D., Tanaka W., Zeng W., et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: A double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin. Ther. 2006;28:55–72. doi: 10.1016/j.clinthera.2006.01.015. PubMed DOI

Kawaguchi T., Kodama T., Hikita H., Makino Y., Saito Y., Tanaka S., Shimizu S., Sakamori R., Miyagi T., Wada H., et al. Synthetic lethal interaction of combined CD26 and Bcl-xL inhibition is a powerful anticancer therapy against hepatocellular carcinoma. Hepatol. Res. Off. J. Jpn. Soc. Hepatol. 2015;45:1023–1033. doi: 10.1111/hepr.12434. PubMed DOI

Yamaguchi T., Watanabe A., Tanaka M., Shiota M., Osada-Oka M., Sano S., Yoshiyama M., Miura K., Kitajima S., Matsunaga S., et al. A dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, attenuates cardiac dysfunction after myocardial infarction independently of DPP-4. J. Pharmacol. Sci. 2019;139:112–119. doi: 10.1016/j.jphs.2018.12.004. PubMed DOI

Batchu S.N., Yerra V.G., Liu Y., Advani S.L., Klein T., Advani A. The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans. Int. J. Mol. Sci. 2020;21:5756. doi: 10.3390/ijms21165756. PubMed DOI PMC

Heo R., Seo M.S., An J.R., Kang M., Park H., Han E.T., Han J.H., Chun W., Park W.S. The anti-diabetic drug trelagliptin induces vasodilation via activation of Kv channels and SERCA pumps. Life Sci. 2021;283:119868. doi: 10.1016/j.lfs.2021.119868. PubMed DOI

Bailey S.R., Nelson M.H., Majchrzak K., Bowers J.S., Wyatt M.M., Smith A.S., Neal L.R., Shirai K., Carpenito C., June C.H., et al. Human CD26(high) T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence. Nat. Commun. 2017;8:1961. doi: 10.1038/s41467-017-01867-9. PubMed DOI PMC

Nelson M.H., Knochelmann H.M., Bailey S.R., Huff L.W., Bowers J.S., Majchrzak-Kuligowska K., Wyatt M.M., Rubinstein M.P., Mehrotra S., Nishimura M.I., et al. Identification of human CD4(+) T cell populations with distinct antitumor activity. Sci. Adv. 2020;6:eaba7443. doi: 10.1126/sciadv.aba7443. PubMed DOI PMC

Casrouge A., Decalf J., Ahloulay M., Lababidi C., Mansour H., Vallet-Pichard A., Mallet V., Mottez E., Mapes J., Fontanet A., et al. Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV. J. Clin. Investig. 2011;121:308–317. doi: 10.1172/JCI40594. PubMed DOI PMC

da Silva R.B., Laird M.E., Yatim N., Fiette L., Ingersoll M.A., Albert M.L. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat. Immunol. 2015;16:850–858. doi: 10.1038/ni.3201. PubMed DOI

Cook S.J., Lee Q., Wong A.C., Spann B.C., Vincent J.N., Wong J.J., Schlitzer A., Gorrell M.D., Weninger W., Roediger B. Differential chemokine receptor expression and usage by pre-cDC1 and pre-cDC2. Immunol. Cell Biol. 2018;96:1131–1139. doi: 10.1111/imcb.12186. PubMed DOI

Wilson A.L., Moffitt L.R., Wilson K.L., Bilandzic M., Wright M.D., Gorrell M.D., Oehler M.K., Plebanski M., Stephens A.N. DPP4 Inhibitor Sitagliptin Enhances Lymphocyte Recruitment and Prolongs Survival in a Syngeneic Ovarian Cancer Mouse Model. Cancers. 2021;13:487. doi: 10.3390/cancers13030487. PubMed DOI PMC

Jang J.H., Janker F., De Meester I., Arni S., Borgeaud N., Yamada Y., Gil Bazo I., Weder W., Jungraithmayr W. The CD26/DPP4-inhibitor vildagliptin suppresses lung cancer growth via macrophage-mediated NK cell activity. Carcinogenesis. 2019;40:324–334. doi: 10.1093/carcin/bgz009. PubMed DOI

Farag S.S., Srivastava S., Messina-Graham S., Schwartz J., Robertson M.J., Abonour R., Cornetta K., Wood L., Secrest A., Strother R.M., et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev. 2013;22:1007–1015. doi: 10.1089/scd.2012.0636. PubMed DOI PMC

Farag S.S., Nelson R., Cairo M.S., O’Leary H.A., Zhang S., Huntley C., Delgado D., Schwartz J., Zaid M.A., Abonour R., et al. High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation. Oncotarget. 2017;8:110350–110357. doi: 10.18632/oncotarget.22739. PubMed DOI PMC

Farag S.S., Abu Zaid M., Schwartz J.E., Thakrar T.C., Blakley A.J., Abonour R., Robertson M.J., Broxmeyer H.E., Zhang S. Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease. N. Engl. J. Med. 2021;384:11–19. doi: 10.1056/NEJMoa2027372. PubMed DOI PMC

Broxmeyer H.E., Hoggatt J., O’Leary H.A., Mantel C., Chitteti B.R., Cooper S., Messina-Graham S., Hangoc G., Farag S., Rohrabaugh S.L., et al. Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat. Med. 2012;18:1786–1796. doi: 10.1038/nm.2991. PubMed DOI PMC

Iwakura T., Zhao Z., Marschner J.A., Devarapu S.K., Yasuda H., Anders H.J. Dipeptidyl peptidase-4 inhibitor teneligliptin accelerates recovery from cisplatin-induced acute kidney injury by attenuating inflammation and promoting tubular regeneration. Nephrol. Dial. Transplant. 2019;34:1669–1680. doi: 10.1093/ndt/gfy397. PubMed DOI

Salama R.M., Nasr M.M., Abdelhakeem J.I., Roshdy O.K., ElGamal M.A. Alogliptin attenuates cyclophosphamide-induced nephrotoxicity: A novel therapeutic approach through modulating MAP3K/JNK/SMAD3 signaling cascade. Drug Chem. Toxicol. 2020;45:1254–1263. doi: 10.1080/01480545.2020.1814319. PubMed DOI

Jo C.H., Kim S., Park J.S., Kim G.H. Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy. Kidney Blood Press. Res. 2018;43:987–999. doi: 10.1159/000490688. PubMed DOI

Mostafa R.E., Morsi A.H., Asaad G.F. Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: Attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury. Res. Pharm. Sci. 2021;16:547–558. doi: 10.4103/1735-5362.323920. PubMed DOI PMC

Iwakura T., Fukasawa H., Kitamura A., Ishibuchi K., Yasuda H., Furuya R. Effect of dipeptidyl peptidase-4 inhibitors on cisplatin-induced acute nephrotoxicity in cancer patients with diabetes mellitus: A retrospective study. PLoS ONE. 2020;15:e0229377. doi: 10.1371/journal.pone.0229377. PubMed DOI PMC

El-Agamy D.S., Abo-Haded H.M., Elkablawy M.A. Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats. Exp. Biol. Med. 2016;241:1577–1587. doi: 10.1177/1535370216643418. PubMed DOI PMC

Aykan D.A., Yaman S., Eser N., Ozcan Metin T., Seyithanoglu M., Aykan A.C., Kurt A.H., Ergun Y. Bisoprolol and linagliptin ameliorated electrical and mechanical isometric myocardial contractions in doxorubicin-induced cardiomyopathy in rats. Pharmacol. Rep. 2020;72:867–876. doi: 10.1007/s43440-019-00034-9. PubMed DOI

Shigematsu N., Kawashiri T., Kobayashi D., Shimizu S., Mine K., Hiromoto S., Uchida M., Egashira N., Shimazoe T. Neuroprotective effect of alogliptin on oxaliplatin-induced peripheral neuropathy in vivo and in vitro. Sci. Rep. 2020;10:6734. doi: 10.1038/s41598-020-62738-w. PubMed DOI PMC

Abo-Haded H.M., Elkablawy M.A., Al-Johani Z., Al-Ahmadi O., El-Agamy D.S. Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity. PLoS ONE. 2017;12:e0174295. doi: 10.1371/journal.pone.0174295. PubMed DOI PMC

Elrashidy R.A., Hasan R.A. Stromal cell-derived factor-1alpha predominantly mediates the ameliorative effect of linagliptin against cisplatin-induced testicular injury in adult male rats. Cytokine. 2020;136:155260. doi: 10.1016/j.cyto.2020.155260. PubMed DOI

Lee J.M., Yoo I.K., Lee J.M., Kim S.H., Choi H.S., Kim E.S., Keum B., Seo Y.S., Jeen Y.T., Chun H.J., et al. Dipeptidyl-peptidase-4 (DPP-4) inhibitor ameliorates 5-flurouracil induced intestinal mucositis. BMC Cancer. 2019;19:1016. doi: 10.1186/s12885-019-6231-y. PubMed DOI PMC

Proost P., Schutyser E., Menten P., Struyf S., Wuyts A., Opdenakker G., Detheux M., Parmentier M., Durinx C., Lambeir A.M., et al. Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties. Blood. 2001;98:3554–3561. doi: 10.1182/blood.V98.13.3554. PubMed DOI

Kuo L.E., Abe K., Zukowska Z. Stress, NPY and vascular remodeling: Implications for stress-related diseases. Peptides. 2007;28:435–440. doi: 10.1016/j.peptides.2006.08.035. PubMed DOI PMC

Yamamoto S., Tokuhara T., Nishikawa M., Nishizawa S., Nishioka T., Nozawa A., Takahashi A., Watanabe Y., Wada R., Wakasa K., et al. Spontaneous regression of hepatocellular carcinoma after improving diabetes mellitus: Possibly responsible for immune system. Kanzo. 2012;53:164–174. doi: 10.2957/kanzo.53.164. DOI

Duarte R.F., Labopin M., Bader P., Basak G.W., Bonini C., Chabannon C., Corbacioglu S., Dreger P., Dufour C., Gennery A.R., et al. Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: Current practice in Europe, 2019. Bone Marrow Transplant. 2019;54:1525–1552. doi: 10.1038/s41409-019-0516-2. PubMed DOI

Sugiyama T., Kohara H., Noda M., Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25:977–988. doi: 10.1016/j.immuni.2006.10.016. PubMed DOI

Peled A., Petit I., Kollet O., Magid M., Ponomaryov T., Byk T., Nagler A., Ben-Hur H., Many A., Shultz L., et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283:845–848. doi: 10.1126/science.283.5403.845. PubMed DOI

Schwaiger E., Klaus C., Matheeussen V., Baranyi U., Pilat N., Ramsey H., Korom S., De Meester I., Wekerle T. Dipeptidyl peptidase IV (DPPIV/CD26) inhibition does not improve engraftment of unfractionated syngeneic or allogeneic bone marrow after nonmyeloablative conditioning. Exp. Hematol. 2012;40:97–106. doi: 10.1016/j.exphem.2011.10.010. PubMed DOI PMC

Kawai T., Choi U., Liu P.C., Whiting-Theobald N.L., Linton G.F., Malech H.L. Diprotin A infusion into nonobese diabetic/severe combined immunodeficiency mice markedly enhances engraftment of human mobilized CD34+ peripheral blood cells. Stem Cells Dev. 2007;16:361–370. doi: 10.1089/scd.2007.9997. PubMed DOI

Kissow H., Hartmann B., Holst J.J., Poulsen S.S. Glucagon-like peptide-1 as a treatment for chemotherapy-induced mucositis. Gut. 2013;62:1724–1733. doi: 10.1136/gutjnl-2012-303280. PubMed DOI

Muscogiuri G., DeFronzo R.A., Gastaldelli A., Holst J.J. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. Trends Endocrinol. Metab. 2017;28:88–103. doi: 10.1016/j.tem.2016.10.001. PubMed DOI

Davidson E.P., Coppey L.J., Dake B., Yorek M.A. Treatment of streptozotocin-induced diabetic rats with alogliptin: Effect on vascular and neural complications. Exp. Diabetes Res. 2011;2011:810469. doi: 10.1155/2011/810469. PubMed DOI PMC

De La Vega M.R., Chapman E., Zhang D.D. NRF2 and the Hallmarks of Cancer. Cancer Cell. 2018;34:21–43. doi: 10.1016/j.ccell.2018.03.022. PubMed DOI PMC

Baek S.H., Kim S.H., Kim J.W., Kim Y.J., Lee K.W., Na K.Y. Effects of a DPP4 inhibitor on cisplatin-induced acute kidney injury: Study protocol for a randomized controlled trial. Trials. 2015;16:239. doi: 10.1186/s13063-015-0772-4. PubMed DOI PMC

Agarwal P., Isringhausen S., Li H., Paterson A.J., He J., Gomariz A., Nagasawa T., Nombela-Arrieta C., Bhatia R. Mesenchymal Niche-Specific Expression of Cxcl12 Controls Quiescence of Treatment-Resistant Leukemia Stem Cells. Cell Stem Cell. 2019;24:769–784.e6. doi: 10.1016/j.stem.2019.02.018. PubMed DOI PMC

Ladikou E.E., Chevassut T., Pepper C.J., Pepper A.G. Dissecting the role of the CXCL12/CXCR4 axis in acute myeloid leukaemia. Br. J. Haematol. 2020;189:815–825. doi: 10.1111/bjh.16456. PubMed DOI

Tavor S., Petit I. Can inhibition of the SDF-1/CXCR4 axis eradicate acute leukemia? Semin. Cancer Biol. 2010;20:178–185. doi: 10.1016/j.semcancer.2010.07.001. PubMed DOI

Devignes C.S., Aslan Y., Brenot A., Devillers A., Schepers K., Fabre S., Chou J., Casbon A.J., Werb Z., Provot S. HIF signaling in osteoblast-lineage cells promotes systemic breast cancer growth and metastasis in mice. Proc. Natl. Acad. Sci. USA. 2018;115:E992–E1001. doi: 10.1073/pnas.1718009115. PubMed DOI PMC

Sleightholm R.L., Neilsen B.K., Li J., Steele M.M., Singh R.K., Hollingsworth M.A., Oupicky D. Emerging roles of the CXCL12/CXCR4 axis in pancreatic cancer progression and therapy. Pharmacol. Ther. 2017;179:158–170. doi: 10.1016/j.pharmthera.2017.05.012. PubMed DOI

Fadini G.P., Avogaro A. Dipeptidyl peptidase-4 inhibition and vascular repair by mobilization of endogenous stem cells in diabetes and beyond. Atherosclerosis. 2013;229:23–29. doi: 10.1016/j.atherosclerosis.2013.04.007. PubMed DOI

Zaruba M.M., Theiss H.D., Vallaster M., Mehl U., Brunner S., David R., Fischer R., Krieg L., Hirsch E., Huber B., et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell. 2009;4:313–323. doi: 10.1016/j.stem.2009.02.013. PubMed DOI

Lee C.S., Kim Y.G., Cho H.J., Park J., Jeong H., Lee S.E., Lee S.P., Kang H.J., Kim H.S. Dipeptidyl Peptidase-4 Inhibitor Increases Vascular Leakage in Retina through VE-cadherin Phosphorylation. Sci. Rep. 2016;6:29393. doi: 10.1038/srep29393. PubMed DOI PMC

Goel S., Duda D.G., Xu L., Munn L.L., Boucher Y., Fukumura D., Jain R.K. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 2011;91:1071–1121. doi: 10.1152/physrev.00038.2010. PubMed DOI PMC

Pan K., Ohnuma K., Morimoto C., Dang N.H. CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions. Cureus. 2021;13:e13495. doi: 10.7759/cureus.13495. PubMed DOI PMC

Mingueneau M., Kreslavsky T., Gray D., Heng T., Cruse R., Ericson J., Bendall S., Spitzer M.H., Nolan G.P., Kobayashi K., et al. The transcriptional landscape of alphabeta T cell differentiation. Nat. Immunol. 2013;14:619–632. doi: 10.1038/ni.2590. PubMed DOI PMC

Najar M., Raicevic G., Fayyad-Kazan H., De Bruyn C., Bron D., Toungouz M., Lagneaux L. Impact of different mesenchymal stromal cell types on T-cell activation, proliferation and migration. Int. Immunopharmacol. 2013;15:693–702. doi: 10.1016/j.intimp.2013.02.020. PubMed DOI

Hinks T.S.C., Zhang X.W. MAIT Cell Activation and Functions. Front. Immunol. 2020;11:1014. doi: 10.3389/fimmu.2020.01014. PubMed DOI PMC

Eble J.A., Niland S. The extracellular matrix in tumor progression and metastasis. Clin. Exp. Metastasis. 2019;36:171–198. doi: 10.1007/s10585-019-09966-1. PubMed DOI

Sadir R., Imberty A., Baleux F., Lortat-Jacob H. Heparan sulfate/heparin oligosaccharides protect stromal cell-derived factor-1 (SDF-1)/CXCL12 against proteolysis induced by CD26/dipeptidyl peptidase IV. J. Biol. Chem. 2004;279:43854–43860. doi: 10.1074/jbc.M405392200. PubMed DOI

Busek P., Mateu R., Zubal M., Kotackova L., Sedo A. Targeting fibroblast activation protein in cancer—Prospects and caveats. Front. Biosci. 2018;23:1933–1968. doi: 10.2741/4682. PubMed DOI

Fitzgerald A.A., Wang S., Agarwal V., Marcisak E.F., Zuo A., Jablonski S.A., Loth M., Fertig E.J., MacDougall J., Zhukovsky E., et al. DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma. J. Immunother. Cancer. 2021;9:e002837. doi: 10.1136/jitc-2021-002837. PubMed DOI PMC