Biomedical Engineering Reference
In-Depth Information
PYY, a potent central stimulator of food intake, is an in vitro substrate of
DPP-4. 109 By cleaving PYY, DPP-4 modifies it to PYY 3-36 . Animal studies
have shown that peripheral administration of PYY 3-36 can suppress food
intake, promote fat oxidation and improve glucose homeostasis. The preven-
tion of the formation of such an endogenous food intake inhibitor and glucose
homeostasis by a DPP-4 inhibitor may be undesirable. However, a recent study
suggests that PYY processing to PYY 3-36 is not essential for its role in glucose
homeostasis. 110
The immunological roles of DPP-4/CD26 have generated debate. 111,112
However, it is unlikely that concern is justified, as the immune role of DPP-4 is
not enzyme-mediated but rather due to protein-protein binding. Thus, inhi-
bition of DPP-4 enzyme activity is unlikely to affect the immune system. 4
Indeed, no significant alterations of immune function have been observed with
DPP-4 inhibitor treatment. 107
The potential effects of non-selective DPP-4 inhibitors on the related
enzymes, DPP-8 and DPP-9, are unclear. The current DPP-4 inhibitors in
clinical use are selective over DPP-8 and DPP-9, but some preclinical studies
have examined non-selective inhibitors. DPP-8 and DPP-9 are ubiquitously
expressed and are thought to have roles in the immune system and cell biology.
An inhibitor of both DPP-8 and DPP-9, and a non-selective DPP-4 inhibitor
have shown severe toxicities in preclinical studies in rodents and dogs, which is
in contrast to DPP-4 selective inhibitors. 113 The toxicity-related outcomes
included alopecia, thrombocytopenia, reticulocytopenia, and splenogamy. 113
The toxic inhibitors produced similar toxicities in DPP-4 deficient and wild type
mice. Thus, the observed toxicities were not due to DPP-4 inhibition. However,
association of such toxicity with DPP-8/DPP-9 inhibition has been disputed by
a recent study that showed that high doses of vildagliptin, at a level that caused
complete inhibition of DPP-8 and DPP-9, did not have any toxic effects on
rodents. 114 Moreover, a different inhibitor of DPP-8 and DPP-9 is non-toxic at
doses that strongly inhibit both proteases. 115 The inhibitors that were asso-
ciated with toxicities have similar chemical structures, 2 so the toxicities may
have been due to the structure of the compounds rather than inhibition of DPP-
8 and DPP-9 enzyme activity. DPP-4 Inhibitor Therapy for Other Diseases
The success of existing DPP-4 inhibitors in clinical use for type 2 diabetes
encourages application to other diseases. The upregulated expression of DPP-4
in tumors makes it a potential marker for particular cancers; however, there is
little direct evidence that DPP-4 inhibitors are likely to be effective in cancer
therapy. The non-selective DPP-4 inhibitor PT100 that inhibits DPP-4, FAP,
DPP-8, and DPP-9 slows tumor growth in mice. 116 In contrast, overexpression
of DPP-4 in a number of cell lines has generally demonstrated anti-tumorigenic
properties, 38,39,117,118 but because similar effects were observed for enzyme
inactive mutants, it is likely that these biological effects of DPP-4 are due to
extra-enzymatic rather than enzymatic function. 1
Search WWH ::

Custom Search