Biomedical Engineering Reference
In-Depth Information
the growth inhibition of human malignant mesothelioma, thus indicating the
potential use of anti-DP4 mAb as a therapeutic in the treatment of DP4-
postiive malignant mesothelioma as well as RCC.
276
In the 2006 study by
Inamoto et al., growth inhibition of RCC resulted from anti-DP4 mAb
induction of G
1
-S cell cycle arrest.
275
In vitro anti-DP4 mAb also resulted in
blocked adhesion of RCC to the ECM presumably due to a increased inter-
nalization of cell surface DP4 leading to a decreased binding capacity of RCC
to collagen and fibronectin.
275
Using a mouse xenograft model of human RCC
in vivo, evidence was provided for the inhibition of tumor growth and enhanced
survival of mice upon anti-DP4 mAb treatment.
275
Research by the same group
had previously shown a similar potential for anti-DP4 mAb in the growth
inhibition of DP4-positive T-cell malignancies via Gs/S cell cycle arrest.
277,278
The development of protein-binding inhibitors is another therapeutic option.
Gonzalez-Gronow et al. demonstrated that the binding of plasminogen to DP4
expressed on the cell surface of 1-LN prostate cancer cells could be blocked
with angiostatin 2e, a peptide fragment of plasminogen.
279
This in turn resulted
in inhibition of the induced intracellular calcium pathway and suppression of
MMP9 expression, and thus invasive capabilities of the cells, suggesting that
the fragment angiostatin 2e may directly block tumor metastasis.
279
For the
development of therapeutics targeting non-enzymatic activities of DP8 and
DP9, further research will need to be performed first to identify any potential
protein binding partners of these intracellular enzymes and whether targeting
these would be a viable option. In the context of the DPs, targeting of the
enzymatic site, or development of DP-resistant substrate analogs, still remains
the most viable option for therapeutic treatment.
1.8 Conclusion
In this review, we have introduced the DPs and placed their rare ability to
cleave the post-prolyl bond in context with other proteases in the human body.
We have provided a thorough overview of the S9b, DP4 gene family, discussing
both homology and gene structure in context with the related PEP and non-
related DP2. An overview of the biochemical features, biological substrates and
the importance of DP4, FAP, DP8, and DP9 to human biology, and disease has
also been discussed followed by issues concerning therapeutic targeting of these
enzymes. While numerous studies of the multifunctional DP4 have, and still are,
being investigated, less is known about the importance of FAP, and even less
still about the intracellular DP8 and DP9. Future studies focusing on eluci-
dating crystal structures for understanding of DP8/9 catalytic mechanism and
development of highly selective inhibitors, along with the generation of DP8
and DP9 knockout animals, will provide us with some of the most valuable
tools for future investigations into the potential physiological and pathological
roles of these proteases. In turn, these may lead to the development of further
therapeutic strategies for the treatment of disease such as cancer, type II dia-
betes, and inflammatory disorders targeting this important enzyme family.
